A pre-therapeutic coating for medical devices that prevents the attachment of Candida albicans.

BACKGROUND: Hospital acquired fungal infections are defined as "never events"-medical errors that should never have happened. Systemic Candida albicans infections results in 30-50% mortality rates. Typically, adhesion to abiotic medical devices and implants initiates such infections. Efficient adhesion initiates formation of aggressive biofilms that are difficult to treat. Therefore, inhibitors of adhesion are important for drug development and likely to have a broad spectrum efficacy against many fungal pathogens. In this study we further the development of a small molecule, Filastatin, capable of preventing C. albicans adhesion. We explored the potential of Filastatin as a pre-therapeutic coating of a diverse range of biomaterials. METHODS: Filastatin was applied on various biomaterials, specifically bioactive glass (cochlear implants, subcutaneous drug delivery devices and prosthetics); silicone (catheters and other implanted devices) and dental resin (dentures and dental implants). Adhesion to biomaterials was evaluated by direct visualization of wild type C. albicans or a non-adherent mutant edt1 -/- that were stained or fluorescently tagged. Strains grown overnight at 30 °C were harvested, allowed to attach to surfaces for 4 h and washed prior to visualization. The adhesion force of C. albicans cells attached to surfaces treated with Filastatin was measured using Atomic Force Microscopy. Effectiveness of Filastatin was also demonstrated under dynamic conditions using a flow cell bioreactor. The effect of Filastatin under microfluidic flow conditions was quantified using electrochemical impedance spectroscopy. Experiments were typically performed in triplicate. RESULTS: Treatment with Filastatin significantly inhibited the ability of C. albicans to adhere to bioactive glass (by 99.06%), silicone (by 77.27%), and dental resin (by 60.43%). Atomic force microcopy indicated that treatment with Filastatin decreased the adhesion force of C. albicans from 0.23 to 0.017 nN. Electrochemical Impedance Spectroscopy in a microfluidic device that mimic physiological flow conditions in vivo showed lower impedance for C. albicans when treated with Filastatin as compared to untreated control cells, suggesting decreased attachment. The anti-adhesive properties were maintained when Filastatin was included in the preparation of silicone materials. CONCLUSION: We demonstrate that Filastatin treated medical devices prevented adhesion of Candida, thereby reducing nosocomial infections.

The role of 5-HT2c receptor on corticosterone-mediated food intake.

Corticosterone plays an important role in feeding behavior. However, its mechanism remains unclear. Therefore, the present study aimed to investigate the effect of corticosterone on feeding behavior. In this study, cumulative food intake was increased by acute corticosterone administration in a dose-dependent manner. Administration of the 5-HT2c receptor agonist m-chlorophenylpiperazin (mCPP) reversed the effect of corticosterone on food intake. The anorectic effects of mCPP were also blocked by the 5-HT2c receptor antagonist RS102221 in corticosterone-treated mice. Both corticosterone and mCPP increased c-Fos expression in hypothalamic nuclei, but not the nucleus of the solitary tract. RS102221 inhibited c-Fos expression induced by mCPP, but not corticosterone. In addition, mCPP had little effect on TH and POMC levels in the hypothalamus. Furthermore, mCPP antagonized decreasing effect of the leptin produced by corticosterone. Taken together, our findings suggest that 5-HT2c receptors and leptin may be involved in the effects of corticosterone-induced hyperphagia.

SEA antagonizes the imatinib-meditated inhibitory effects on T cell activation via the TCR signaling pathway.

The BCR-ABL kinase inhibitor imatinib is highly effective in the treatment of chronic myeloid leukemia (CML). However, long-term imatinib treatment induces immunosuppression, which is mainly due to T cell dysfunction. Imatinib can reduce TCR-triggered T cell activation by inhibiting the phosphorylation of tyrosine kinases such as Lck, ZAP70, LAT, and PLC γ 1 early in the TCR signaling pathway. The purpose of this study was to investigate whether the superantigen SEA, a potent T cell stimulator, can block the immunosuppressive effects of imatinib on T cells. Our data show that the exposure of primary human T cells and Jurkat cells to SEA for 24 h leads to the upregulation of the Lck and ZAP70 proteins in a dose-dependent manner. T cells treated with SEA prior to TCR binding had increased the tyrosine phosphorylation of Lck, ZAP70, and PLC γ 1. Pretreatment with SEA prevents the inhibitory effects of imatinib on TCR signaling, which leads to T cell proliferation and IL-2 production. It is conceivable that SEA antagonizes the imatinib-mediated inhibition of T cell activation and proliferation through the TCR signaling pathway.

What is the risk of intensifying platelet inhibition beyond clopidogrel? A systematic review and a critical appraisal of the role of prasugrel.

Thienopyridines are a class of drug targeting the platelet adenosine diphosphate 2 receptor. They have been shown to significantly reduce platelet activity exerting an important role in those clinical settings in which such an effect is beneficial. Ticlopidine was first to be introduced several years ago but it was quickly replaced by clopidogrel as it had a better risk/benefit profile. Recently, prasugrel has been developed and tested in several ex vivo studies and clinical trials showing able to provide a more powerful antiplatelet effect at the expense of a higher risk of bleeding complications. Great debate rose around its recent approval in the US as well as in Europe. This review aims at exploring the development and available clinical data of this third-generation thienopyridine while discussing its practical implementation in routine practice.

[Evaluation of supplemental administration of Eviprostat in patients with benign prostatic hyperplasia with persistent symptoms following treatment with alpha1-adrenoceptor blocker].

We examined the effectiveness of supplemental administration of Eviprostat in patients with benign prostatic hyperplasia (BPH) whose lower urinary tract symptoms (LUTS) caused by BPH were not adequately relieved by an alpha1-adrenoceptor blocker. Twenty-nine patients with insufficient improvement in the International Prostate Symptom Score (IPSS) and quality of life (QOL) score after administration of 50 mg naftopidil for 4 weeks or more received 6 tablets of Eviprostat in addition to naftopidil for another 2 weeks or more. With supplemental administration of Eviprostat, significant improvement was observed in the symptoms of incomplete emptying, daytime frequency, intermittency, weak stream, total IPSS, sum of the IPSS subscores for voiding symptoms (intermittency, weak stream and straining), sum of the IPSS subscores for storage symptoms (daytime frequency, urgency and nocturia), and QOL score. Supplemental administration of Eviprostat is therefore effective for the improvement of LUTS and QOL in BPH patients resistant to an alpha1-adrenoceptor blocker.

Effect of imatinib mesylate combined with granulocyte colony-stimulating factor on leukaemic blast cells derived from advanced-stage chronic myelogenous leukaemia patients.

Neutropenia is a severe adverse effect that can occur when treating patients with imatinib mesylate for advanced-stage chronic myelogenous leukaemia (CML). Therefore, we evaluated in vitro the combined effect of imatinib and granulocyte colony-stimulating factor (G-CSF) on proliferation and apoptosis of Bcr-Abl-expressing leukaemic cells to infer the safety of G-CSF administration. In KU812 and K562 cell lines, G-CSF neither stimulated their proliferation nor abolished the suppressive effect of imatinib. However, it stimulated the proliferation of blast cells in 2 out of the 5 cases with advanced-stage CML. These in vitro studies appear to provide data for the decision of G-CSF administration in combination with imatinib in the treatment of neutropenic patients with advanced-stage CML.

Differential regional antagonism of 8-OH-DPAT-induced decrease in serotonin synthesis by two 5-HT1A receptor antagonists.

The effects of two 5-HT1A receptor antagonists, (R)-3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2 H-1-benzopyran-5-carboxamide hydrogen (2 R,3 R)-tartrate monohydrate (NAD-299) and N-(2-(1-(2-methoxyphenyl)-piperazinyl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY-100635) on the decrease in 5-hydroxytryptophan (5-HTP) accumulation evoked by (RS)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene (8-OH-DPAT) in rats treated with the decarboxylase inhibitor, 3-hydroxyphenylhydrazine (NSD 1015) were studied in four rat brain regions: hippocampus, hypothalamus, striatum and frontal cortex. Dose-response studies revealed differential effects of both antagonists in the areas examined. Both antagonists were significantly more potent in antagonising the effect of 0.30 and 0.76 micromol/kg s.c. 8-OH-DPAT in hippocampus than in hypothalamus, striatum and frontal cortex in mentioned order. This order of potency was the opposite to that found for 8-OH-DPAT in decreasing the 5-HTP accumulation. Since previous studies by others have indicated that the reserve of somatodendritic 5-HT1A receptors is greater in dorsal raphe nucleus innervating frontal cortex and striatum than in median raphe nucleus which mainly innervates hippocampus, the observed different regional potency of the two 5-HT1A receptor antagonists may be explained by this difference in the 5-HT1A receptor reserve.

mCPP-induced anxiety in the light-dark box in rats--a new method for screening anxiolytic activity.

The activity of anxiolytic and other drugs in a light-dark test situation was studied in rats treated with the anxiogenic compound m-chlorophenyl-piperazine (mCPP). mCPP 0.5 mg/kg significantly diminished the exploratory activity of the animals in the light compartment of the apparatus. Drugs to be tested against mCPP-induced anxiety when studied alone (not in combination with mCPP) did not significantly alter the activity of rats in the light-dark apparatus, except yohimbine, which reduced the movement time values in the lit area. 1,4-Benzodiazepines [diazepam (0.1-4mg/kg) and chlordiazepoxide (2-8mg/kg)], 5-HT2A/2C antagonists [ritanserin (0.25-8 mg/kg) and deramciclane (0.5-8 g/kg)], the 5-HT3 antagonist MDL-72222 (3 mg/kg) and ethanol (2-4 mg/kg) significantly reduced the effect of mCPP. A dose-dependent increase in the exploratory activity of mCPP-treated animals was found in the 2,3-benzodiazepine girisopam (2.5-5 mg/kg)-treated groups. Tofisopam, another 2,3-benzodiazepine molecule, also showed activity against mCPP, although its effect was not statistically significant. The 5-HT1A partial agonist buspirone was also active in the dose range of 0.25-0.5 mg/kg, while the 5-HT1A full agonist 8-OH-DPAT was the only drug with presumed anxiolytic activity that clearly lacked any effect in this model. Imipramine, amitriptyline, morphine, naloxone, haloperidol, clozapine, amphetamine, yohimbine, carbamazepine and diphenylhydantoin were not effective. We conclude that mCPP-induced anxiety in the light-dark box is a potent and useful method for screening and detecting anxiolytic activity of a wide range of compounds with various modes of action.

Role of endogenous cyclo(His-Pro) in cold-induced hypothermia in the desert rat (Mastomys natalensis).

Central administration of exogenous cyclo(His-Pro) (CHP) is known to produce hypothermia in rodents. In the present study, we examined the role of endogenous CHP in cold-induced hypothermia in the desert rat, Mastomys natalensis. The results of these studies show that a rise in hypothalamic CHP content accompanied a decrease in rectal temperature during cold exposure. Immunoneutralization of endogenous CHP resulted in a significant decline in cold-induced hypothermia. In addition, central administration of cyclo(Ala-Gly), a structural analogue of CHP, also led to a decrease in cold-induced hypothermia. The results of these studies show that changes in endogenous CHP levels may affect body temperature regulation.