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Aim: To evaluate the antifungal activity of amlodipine against strains of Candida spp. and to its possible mechanism of action.Methods: Broth microdilution tests were used to determine the minimum inhibitory concentration, while the synergistic activity was evaluated by calculating the fractional inhibitory concentration index. The action of amlodipine against biofilms was determined using the MTT assay and its possible mechanism of action was investigated through flow cytometry tests.Results: Amlodipine showed MICs ranging from 62.5 to 250 µg/ml, in addition to action against pre-formed and forming biofilms, with reductions between 50 and 90%. Amlodipine increases the externalization of phosphatidylserine and reduces the cell viability of fungal cells, suggesting apoptosis.Conclusion: Amlodipine had good antifungal activity against planktonic cells and biofilms of Candida spp., by leading the cells to apoptosis.

Candida is a type of fungus that can cause diseases. This fungus became stronger over time and drugs can no longer kill them easily, so it is important to find new drugs. We decided to study whether amlodipine, a drug used for heart disease, has action against Candida. We discovered that amlodipine make fungi weaker. We still need to do more studies to find out if amlodipine can help prevent Candida diseases.

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Mammalian and reptilian vascular tissues present basal release of 6-nitrodopamine, which is reduced when the tissues are pre-incubated with the NO synthase inhibitor L-NG-Nitro arginine methyl ester (L-NAME), or when the endothelium is mechanically removed. 6-Nitrodopamine induces vasorelaxation in pre-contracted vascular rings by antagonizing the dopaminergic D2-like receptor. Here it was investigated whether male swine vessels (including carotid, left descendent coronary, renal, and femoral arteries) release 6-nitrodopamine, dopamine, noradrenaline, and adrenaline, as measured by liquid chromatography coupled to tandem mass spectrometry. The in vitro vasorelaxant action of 6-nitrodopamine was evaluated in carotid, coronary, renal, and femoral arteries precontracted by U-46619 (3 nM), and compared to that induced by the dopamine D2-receptor antagonist L-741,626. Expression of tyrosine hydroxylase and the neuromaker calretinin was investigated by immunohistochemistry. All vascular tissues presented basal release of endothelium-derived catecholamines. The relaxation induced by 6-nitrodopamine was not affected by preincubation of the tissues with either L-NAME (100 µM, 30-min preincubation) or the heme-site inhibitor of soluble guanylyl cyclase ODQ (100 µM, 30-min preincubation). Electrical field stimulation (EFS)-induced contractions were significantly potentiated by previous incubation with L-NAME, but unaffected by ODQ preincubation. The contractions induced by EFS were reduced by preincubation with either 6-nitrodopamine or L-741,626. Immunohistochemistry in all arteries revealed the presence of tyrosine hydroxylase in the endothelium, whereas immunoreactivity for calretinin was negative. Swine vessels present basal release of endothelium-derived catecholamines and expression of tyrosine hydroxylase in the endothelium. The vasodilation induced by 6-nitrodopamine is due to blockade of dopaminergic D2-like receptors.

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Candida species are among the priority pathogens in the area of research and development. Due to the problems associated with resistance to antifungals, new therapeutic alternatives are necessary. In this regard, drug repositioning has gained prominence. The objective of this study was to evaluate the activity of three tricyclic antidepressants (TCAs) - amitriptyline (AMT), nortriptyline (NOR) and clomipramine (CLO) - isolated or associated with antifungals against strains of Candida spp., as well as to analyze the possible mechanism of action. Among the methods used were broth microdilution tests, tolerance level assessment, checkerboard assays, flow cytometry and fluorescence microscopy. Furthermore, Candida cells were visualized after treatments by scanning electron microscopy (SEM). AMT presented MIC 50% in the range of 16 to 128 µg/mL, NOR from 8 to 128 µg/mL, and CLO from 8 to 64 µg/mL, with all three TCAs having a fungicidal inhibitory action profile. For these TCAs, there was synergism with amphotericin B (AMB) in 100% of the isolates. In association with fluconazole (FLC) and itraconazole (ITR), there were mostly indifferent interactions. TCAs isolated and associated with AMB reduced cell viability, promoted DNA fragmentation and damage, caused mitochondrial depolarization, externalization of phosphatidylserine, produced reactive oxygen species (ROS), decreased reduced glutathione (GSH) and increased carbonyl protein levels, causing morphological changes. The results suggest the antifungal mechanism of the TCAs works via the apoptotic pathway.

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The increase in fungal resistance is a major public health concern. In this context, Candida spp. is an important genus related to invasive diseases, especially in immunosuppressed patients. The relevance of alternative approaches to increasing fungal resistance stands out, in which products of natural origin demonstrate potential antifungal activity in vitro against Candida spp. In this sense, this work aimed to evaluate the in vitro activity of tannic acid against Candida spp. Minimum inhibitory concentration (MIC) was determined for tannic acid and the antifungals, and the checkerboard assay was performed to analyze the interactions between them. Furthermore, we evaluated the tannic acid antibiofilm activity and its possible mechanism of action. Tannic acid showed MIC ranging to 0.06 to 0.5 µg/ml and showed no loss of effectiveness when combined with antifungals. Also, is safe at the concentrations it exerts its antifungal activity in pre-formed biofilms, as demonstrated by IC50 in murine fibroblasts cells and the hemolytic assay. Additionally, its mechanisms of action can be related with induction of signals that lead to apoptosis in fungal cells.

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Aim: Evaluate the anticandidal effect of Croton heliotropiifolius Kunth essential oil and its interaction with azoles and N-acetylcysteine (NAC) against planktonic cells and biofilms. Materials & methods: Broth microdilution and checkerboard methods were used to evaluate the individual and combined activity with fluconazole and itraconazole (ITRA). The antibiofilm effect of the oil was assessed in 96-well plates alone and combined with ITRA and NAC, and cytotoxicity determined by MTT. Results: The oil inhibited all Candida species growth. The activity was enhanced when associated with ITRA and NAC for planktonic cells and biofilms in formation. The effective concentrations were lower than the toxic ones to V79 cells. Conclusion: C. heliotropiifolius Kunth essential oil is an anticandidal alternative, and can be associated with ITRA and NAC.

Candida is a type of fungus that can cause disease in people. In recent years, the number of available drugs to treat this disease have declined. It is important to search for new drugs. Plants are often used to improve health, so we tested the essential oil of a plant called Croton heliotropiifolius to see if it could kill the fungus. We found that the essential oil could kill the fungus, and could be used with other drugs to improve their effects.

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Introduction. The development of new antifungal drugs has become a global priority, given the increasing cases of fungal diseases together with the rising resistance to available antifungal drugs. In this scenario, drug repositioning has emerged as an alternative for such development, with advantages such as reduced research time and costs.Gap statement. Propafenone is an antiarrhythmic drug whose antifungal activity is poorly described, being a good candidate for further study.Aim. This study aims to evaluate propafenone activity against different species of Candida spp. to evaluate its combination with standard antifungals, as well as its possible action mechanism.Methodology. To this end, we carried out tests against strains of Candida albicans, Candida auris, Candida parapsilosis, Candida tropicalis, Candida glabrata and Candida krusei based on the evaluation of the MIC, minimum fungicidal concentration and tolerance level, along with checkerboard and flow cytometry tests with clinical strains and cell structure analysis by scanning electron microscopy (SEM).Results. The results showed that propafenone has a 50% MIC ranging from 32 to 256 µg ml-1, with fungicidal activity and positive interactions with itraconazole in 83.3% of the strains evaluated. The effects of the treatments observed by SEM were extensive damage to the cell structure, while flow cytometry revealed the apoptotic potential of propafenone against Candida spp.Conclusion. Taken together, these results indicate that propafenone has the potential for repositioning as an antifungal drug.

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Aim: To evaluate the antifungal activity of mangiferin against Candida spp. resistant to fluconazole.Materials & methods: The antifungal activity of mangiferin was assessed using broth microdilution and its interaction with azoles and amphotericin B was evaluated by checkerboard. The activity of mangiferin against Candida spp. biofilms was assessed using the MTT colorimetric assay and its possible mechanism of action was evaluated using flow cytometry.Results: Mangiferin showed activity against Candida albicans, Candida tropicalis and Candida parapsilosis resistant to fluconazole and showed synergism with azoles and amphotericin B. Mangiferin increased the activity of antifungals against Candida biofilms and caused depolarization of the mitochondrial membrane and externalization of phosphatidylserine, suggesting apoptosis.Conclusion: mangiferin combined with antifungals has potential against Candida spp.

Candida is a type of fungus that can make people ill. Over time, many species of Candida have found ways to resist the drugs used to kill them. It is important to find new drugs. We decided to see if a substance called mangiferin works against Candida. We found that mangiferin works against Candida and may help other drugs to work better. We still need to do more studies to find out whether mangiferin can help prevent diseases caused by Candida in the future.

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In the present study, the effect of sulfonamide-chalcone 185 (SSC185) was investigated against B16-F10 metastatic melanoma cells aggressive actions, besides migration and adhesion processes, by in silico and in vitro assays. In silico studies were used to characterize the pharmacokinetic profile and possible targets of SSC185, using the pkCSM web server, and docking simulations with AutoDock Tools. Furthermore, the antimetastatic effect of SSC185 was investigated by in vitro experiments using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide), colony, scratch, and cell adhesion assays, and atomic force microscopy (AFM). The molecular docking results show better affinity of SSC185 with the metalloproteinases-2 (MMP-2) and α5ß1 integrin. SSC185 effectively restricts the formation of colonies, migration, and adhesion of B16-F10 metastatic melanoma cells. Through the AFM images changes in cells morphology was identified, with a decrease in the filopodia and increase in the average cellular roughness. The results obtained demonstrate the potential of this molecule in inhibit the primordial steps for metastasis, which is responsible for a worse prognosis of late stage cancer, being the main cause of morbidity among cancer patients.

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Aim: The present study investigated the antimicrobial effectiveness of a rhamnolipid complexed with arginine (RLMIX_Arg) against planktonic cells and biofilms of methicillin-resistant Staphylococcus aureus (MRSA). Methodology: Susceptibility testing was performed using the Clinical & Laboratory Standards Institute protocol: M07-A10, checkerboard test, biofilm in plates and catheters and flow cytometry were used. Result: RLMIX_Arg has bactericidal and synergistic activity with oxacillin. RLMIX_Arg inhibits the formation of MRSA biofilms on plates at sub-inhibitory concentrations and has antibiofilm action against MRSA in peripheral venous catheters. Catheters impregnated with RLMIX_Arg reduce the formation of MRSA biofilms. Conclusion: RLMIX_Arg exhibits potential for application in preventing infections related to methicillin-resistant S. aureus biofilms.

[Box: see text].

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AIMS: This study aimed to investigate the effects of Umbelliferone (UMB) on the inflammation underlying alveolar bone resorption in mouse periodontitis. METHODS: Male Swiss mice subjected to a ligature of molars were grouped as non-treated (NT), received UMB (15, 45, or 135 mg/kg) or saline daily for 7 days, respectively, and were compared with naïve mice as control. Gingival tissues were evaluated by myeloperoxidase (MPO) activity and interleukin-1ß level by ELISA. The bone resorption was directly assessed on the region between the cement-enamel junction and the alveolar bone crest. Microscopically, histomorphometry of the furcation region, immunofluorescence for nuclear factor-kappa B (NF-ĸB), and immunohistochemistry for tartrate-resistant acid phosphatase (TRAP), and cathepsin K (CTSK) were performed. Systemically, body mass variation and leukogram were analyzed. RESULTS: Periodontitis significantly increased MPO activity, interleukin-1ß level, and NF-ĸB+ immunofluorescence, and induced severe alveolar bone and furcation resorptions, besides increased TRAP+ and CTSK+ cells compared with naïve. UMB significantly prevented the inflammation by reducing MPO activity, interleukin-1ß level, and NF-ĸB+ intensity, besides reduction of resorption of alveolar bone and furcation area, and TRAP+ and CTSK+ cells compared with the NT group. Periodontitis or UMB treatment did not affect the animals systemically. CONCLUSION: UMB improved periodontitis by reducing inflammation and bone markers.

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Background: Staphylococcus aureus is a human pathogen responsible for high mortality rates. The development of new antimicrobials is urgent. Materials & methods: The authors evaluated the activity of hydralazine along with its synergism with other drugs and action on biofilms. With regard to action mechanisms, the authors evaluated cell viability, DNA damage and molecular docking. Results: MIC and minimum bactericidal concentration values ranged from 128 to 2048 µg/ml. There was synergism with oxacillin (50%) and vancomycin (25%). Hydralazine reduced the viability of biofilms by 50%. After exposure to hydralazine 2× MIC, 58.78% of the cells were unviable, 62.07% were TUNEL positive and 27.03% presented damage in the comet assay (p < 0.05). Hydralazine showed affinity for DNA gyrase and TyrRS. Conclusion: Hydralazine is a potential antibacterial.

Staphylococcus aureus is a bacterium that can cause infection. Infections of S. aureus are becoming difficult to treat, but developing new drugs is a challenge. Repurposing them may be easier. This study looks at the possibility of using hydralazine, a type of medicine used to treat high blood pressure, against S. aureus. The authors found that hydralazine can kill S. aureus and can be used with other antibiotics, including oxacillin and vancomycin. Hydralazine interferes with important processes for the multiplication and survival of this bacterium. These results are preliminary but encouraging. Further studies are needed to confirm the use of hydralazine as a new treatment for S. aureus infections.

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Croton heliotropiifolius Kunth, popularly known as "velame," is a shrub that resides in northeastern Brazil. The essential oil of C. heliotropiifolius contains high concentrations of volatile compounds in the leaves and is widely used in folk medicine for many purposes as an antiseptic, analgesic, sedative, and anti-inflammatory agent. Due to the apparent limited amount of information, the aim of this study was to determine the cytotoxic potential of essential oil extracted from leaves of C. heliotropiifolius, utilizing different human cancer cell lines (HL-60, leukemia; HCT-116, colon; MDA-MB435, melanoma; SF295, glioblastoma) and comparison to murine fibroblast L929 cell line. The chemical characterization of the essential oil revealed the presence of large amounts of monoterpenes and sesquiterpenes, the majority of which were aristolene (22.43%), germacrene D (11.38%), ɣ-terpinene (10.85%), and limonene (10.21%). The essential oil exerted significant cytotoxicity on all cancer cells, with low activity on murine L929 fibroblasts, independent of disruption of cell membranes evidenced by absence of hemolytic activity. The cytotoxicity identified was associated with oxidative stress, which culminated in mitochondrial respiration dysfunction and direct or indirect DNA damage (strand breaks and oxidative damage), triggering cell death via apoptosis. Our findings suggest that extracts of essential oil of C. Heliotropiifolius may be considered as agents to be used therapeutically in treatment of certain cancers.

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BACKGROUND: 6-Nitrodopamine (6-ND) is a novel endogenous catecholamine that has a potent relaxant action on vascular smooth muscle in vitro. OBJECTIVES: To evaluate the basal release of 6-ND and noradrenaline from rabbit-isolated corpus cavernosum (RbCC) and its relaxing action on this tissue. METHODS: Rabbit corpus cavernosa were dissected and suspended in a 5-mL organ bath containing oxygenated Krebs-Henseleit's solution. 6-ND and noradrenaline release was quantified by liquid chromatography coupled to tandem mass spectrometry. The relaxant activity of 6-ND was assessed in RbCC strips pre-contracted with endothelin-1 (10 nM). RESULTS: Rabbit corpus cavernosum presented basal release of both 6-ND (2.9 ± 0.8 ng/mL, n = 12) and noradrenaline (1.7 ± 1.3 ng/mL, n = 12). The 6-ND release was reduced by pre-treatment with Nω-nitro-l-arginine methyl ester (l-NAME) (100 µM), whereas that of noradrenaline was unaffected. Tetrodotoxin (TTX, 1 µM) abolished the noradrenaline release but had no effect on 6-ND release, indicating a non-neurogenic origin for 6-ND. 6-ND and the selective dopamine D2-agonist L-741,626 caused concentration-dependent RbCC relaxations (pEC50 of 11 ± 0.15 and 11.15 ± 0.28, respectively). Pre-treatment with either l-NAME or the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-on (ODQ) (100 µM) caused a rightward shift of the concentration-response curve to 6-ND, without affecting the L-741,626 responses. In TTX (100 nM)-pre-treated preparations, neither l-NAME nor ODQ shifted the 6-ND concentration-response curve. Dopamine, noradrenaline, and adrenaline caused concentration-dependent RbCC contractions. Pre-incubation with 6-ND concentration-dependently inhibited the dopamine-induced contractions, without affecting those induced by either noradrenaline or adrenaline. DISCUSSION AND CONCLUSION: 6-Nitrodopamine is the most potent endogenous relaxant agent in RbCC ever described and represents a novel mechanism by which NO causes corpus cavernosum smooth muscle relaxation. The finding that 6-ND acts as a truly selective dopamine D2-receptor antagonist indicates that the balance of dopamine and 6-ND release/synthesis may be the main mechanism that modulates corpus cavernosum smooth muscle tonus in vivo.

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BACKGROUND: 6-nitrodopamine released from rat isolated atria exerts positive chronotropic action, being more potent than noradrenaline, adrenaline, and dopamine. Here, we determined whether 6-nitrodopamine is released from rat isolated ventricles (RIV) and modulates heart inotropism. METHODS: Catecholamines released from RIV were quantified by LC-MS/MS and their effects on heart inotropism were evaluated by measuring left ventricular developed pressure (LVDP) in Langendorff's preparation. RESULTS: 6-nitrodopamine was the major released catecholamine from RIV. Incubation with L-NAME (100 µM), but not with tetrodotoxin (1 µM), caused a significant reduction in 6-nitrodopamine basal release. 6-nitrodopamine release was significantly reduced in ventricles obtained from L-NAME chronically treated animals. 6-nitrodopamine (0.01 pmol) caused significant increases in LVDP and dP/dtmax, whereas dopamine and noradrenaline required 10 pmol, and adrenaline required 100 pmol, to induce similar increases in LVDP and dP/dtmax. The infusion of atenolol (10 nM) reduced basal LVDP and blocked the increases in LVDP induced by 6-ND (0.01 pmol), without affecting the increases in LVDP induced by 10 nmol of dopamine and noradrenaline and that induced by adrenaline (100 nmol). CONCLUSIONS: 6-nitrodopamine is the major catecholamine released from rat isolated ventricles. It is 1000 times more potent than dopamine and noradrenaline and is selectively blocked by atenolol, indicating that 6-ND is a main regulator of heart inotropism.

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Species of the genus Candida, characterized as commensals of the human microbiota, are opportunistic pathogens capable of generating various types of infections with high associated costs. Considering the limited pharmacological arsenal and the emergence of antifungal-resistant strains, the repositioning of drugs is a strategy used to search for new therapeutic alternatives, in which minocycline and doxycycline have been evaluated as potential candidates. Thus, the objective was to evaluate the in vitro antifungal activity of two tetracyclines, minocycline and doxycycline, and their possible mechanism of action against fluconazole-resistant strains of Candida spp. The sensitivity test for antimicrobials was performed using the broth microdilution technique, and the pharmacological interaction with fluconazole was also analysed using the checkerboard method. To analyse the possible mechanisms of action, flow cytometry assays were performed. The minimum inhibitory concentration obtained was 4-427 µg ml-1 for minocycline and 128-512 µg ml-1 for doxycycline, and mostly indifferent and additive interactions with fluconazole were observed. These tetracyclines were found to promote cellular alterations that generated death by apoptosis, with concentration-dependent reactive oxygen species production and reduced cell viability. Therefore, minocycline and doxycycline present themselves as promising study molecules against Candida spp.

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Fungal infections caused by Cryptococcus spp. pose a threat to health, especially in immunocompromised individuals. The available arsenal of drugs against cryptococcosis is limited, due to their toxicity and/or lack of accessibility in low-income countries, requiring more therapeutic alternatives. Selective serotonin reuptake inhibitors (SSRIs), through drug repositioning, are a promising alternative to broaden the range of new antifungals against Cryptococcus spp. This study evaluates the antifungal activity of three SSRIs, sertraline, paroxetine, and fluoxetine, against Cryptococcus spp. strains, as well as assesses their possible mechanism of action. Seven strains of Cryptococcus spp. were used. Sensitivity to SSRIs, fluconazole, and itraconazole was evaluated using the broth microdilution assay. The interactions resulting from combinations of SSRIs and azoles were investigated using the checkerboard assay. The possible action mechanism of SSRIs against Cryptococcus spp. was evaluated through flow cytometry assays. The SSRIs exhibited in vitro antifungal activity against Cryptococcus spp. strains, with minimum inhibitory concentrations ranging from 2 to 32 µg/mL, and had synergistic and additive interactions with azoles. The mechanism of action of SSRIs against Cryptococcus spp. involved damage to the mitochondrial membrane and increasing the production of reactive oxygen species, resulting in loss of cellular viability and apoptotic cell death. Fluoxetine also was able to cause significant damage to yeast DNA. These findings demonstrate the in vitro antifungal potential of SSRIs against Cryptococcus spp. strains.

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Introduction. Antibiotic resistance is a major threat to public health, particularly with methicillin-resistant Staphylococcus aureus (MRSA) being a leading cause of antimicrobial resistance. To combat this problem, drug repurposing offers a promising solution for the discovery of new antibacterial agents.Hypothesis. Menadione exhibits antibacterial activity against methicillin-sensitive and methicillin-resistant S. aureus strains, both alone and in combination with oxacillin. Its primary mechanism of action involves inducing oxidative stress.Methodology. Sensitivity assays were performed using broth microdilution. The interaction between menadione, oxacillin, and antioxidants was assessed using checkerboard technique. Mechanism of action was evaluated using flow cytometry, fluorescence microscopy, and in silico analysis.Aim. The aim of this study was to evaluate the in vitro antibacterial potential of menadione against planktonic and biofilm forms of methicillin-sensitive and resistant S. aureus strains. It also examined its role as a modulator of oxacillin activity and investigated the mechanism of action involved in its activity.Results. Menadione showed antibacterial activity against planktonic cells at concentrations ranging from 2 to 32 µg ml-1, with bacteriostatic action. When combined with oxacillin, it exhibited an additive and synergistic effect against the tested strains. Menadione also demonstrated antibiofilm activity at subinhibitory concentrations and effectively combated biofilms with reduced sensitivity to oxacillin alone. Its mechanism of action involves the production of reactive oxygen species (ROS) and DNA damage. It also showed interactions with important targets, such as DNA gyrase and dehydroesqualene synthase. The presence of ascorbic acid reversed its effects.Conclusion. Menadione exhibited antibacterial and antibiofilm activity against MRSA strains, suggesting its potential as an adjunct in the treatment of S. aureus infections. The main mechanism of action involves the production of ROS, which subsequently leads to DNA damage. Additionally, the activity of menadione can be complemented by its interaction with important virulence targets.

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6-nitrodopamine (6-ND) is released from rat isolated atria, where it acts as a potent positive chronotropic agent. The release of 6-ND from rat isolated atria and ventricles is significantly reduced when pre-incubated with l-NAME, and the release was not affected by tetrodotoxin pre-treatment, indicating that in the heart, the origin of 6-ND is not neurogenic. Since l-NAME inhibits all three isoforms of NO synthase, it was investigated the basal release of 6-ND from isolated atria and ventricles from nNOS-/-, iNOS-/- and eNOS-/- mice of either sex. The release of 6-ND was measured by LC-MS/MS. There were no significant differences in the 6-ND basal release from isolated atria and ventricles from male control mice, as compared to female control mice. The 6-ND release from atria obtained from eNOS-/- mice was significantly reduced when compared to atria obtained from control mice. The 6-ND release in nNOS-/- mice was not significantly different compared to control animals whereas the 6-ND release from atria obtained from iNOS-/- mice was significantly higher when compared to control group. Incubation of the isolated atria with l-NAME caused a significant decrease in the basal atrial rate of control, nNOS-/-, and iNOS-/- mice, but not in eNOS-/- mice. The results clearly indicate that eNOS is the isoform responsible for the synthesis of 6-ND in the mice isolated atria and ventricles and supports the concept that 6-ND is the major mechanism by which endogenous NO modulates heart rate.

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6-Nitrodopamine (6-ND) is a novel catecholamine that is released from human umbilical cord vessels, and it causes vascular relaxation by acting as a dopamine D2-receptor antagonist. Here it was investigated whether human peripheral vessels obtained from patients who have undergone surgery for leg amputation release 6-ND, and its action in these tissues. Popliteal artery and vein strips present basal release of 6-ND, as measured by liquid chromatography coupled to tandem mass spectrometry. The release was significantly reduced when the tissues were pre-treated with the nitric oxide synthase inhibitor L-NAME (100 µM), or when the endothelium was mechanically removed. In U-46619 (3 nM) pre-contracted rings, 6-ND induced concentration-dependent relaxations (pEC50 8.18 ± 0.05 and 8.40 ± 0.08, in artery and vein rings, respectively). The concentration-dependent relaxations induced by 6-ND were unaffected in tissues pre-treated with L-NAME, but significantly reduced in tissues where the endothelium has been mechanically removed. In U-46619 (3 nM) pre-contracted rings, the selective dopamine D2 receptor antagonist L-741,626 also caused concentration-dependent relaxations (pEC50 8.92 ± 0.22 and 8.79 ± 0.19, in artery and vein rings, respectively). The concentration-dependent relaxations induced by L-741,626 were unaffected in tissues pre-treated with L-NAME, but significantly reduced in tissues where the endothelium has been mechanically removed. This is the first demonstration that 6-nitrodopamine is released from human peripheral artery and vein rings. The results also indicate that endothelium-derived dopamine is a major contractile agent in the popliteal artery and vein, and that selective dopamine D2-receptor antagonists such as 6-ND, may have therapeutic potential in the treatment of human peripheral vascular diseases.

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Candida spp. infections are a serious health problem, especially in patients with risk factors. The acquisition of resistance, often associated with biofilm production, makes treatment more difficult due to the reduced effectiveness of available antifungals. Drug repurposing is a good alternative for the treatment of infections by Candida spp. biofilms. The present study evaluated the in vitro antibiofilm activity of sertraline in reducing the cell viability of forming and matured biofilms, in addition to elucidating whether effective concentrations are safe. Sertraline reduced biofilm cell viability by more than 80 % for all Candida species tested, acting at low and safe concentrations, both on mature biofilm and in preventing its formation, even the one with highest virulence. Its preventive mechanism seemed to be related to binding with ALS3. These data indicate that sertraline is a promising drug with anticandidal biofilm potential in safe doses. However, further studies are needed to elucidate the antibiofilm mechanism and possible application of pharmaceutical forms.

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