965 resultados para Anti-mitotic Agents
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Allergic rhinitis is one of the most common clinical conditions in children; however, data regarding the safety of antihistamines in children with seasonal allergic rhinitis are limiting. To evaluate the safety and efficacy of fexofenadine in children with seasonal allergic rhinitis, data were pooled from three, double-blind, randomized, placebo-controlled, parallel-group, 2-week trials in children (6-11 year) with seasonal allergic rhinitis. All studies assessed fexofenadine HCl 30 mg b.i.d.; two studies included fexofenadine HCl at 15 and 60 mg b.i.d. Patients (and investigators) reported any adverse events during the trial. Physical examinations, including measurements of vital signs and laboratory tests, were performed. Efficacy assessments (total symptom score and individual symptom scores) were evaluated. Exposure to fexofenadine HCl 30 mg b.i.d. and to any fexofenadine dose exceeded 10,000 and 17,000 patient days, respectively. Incidences of adverse events, and discontinuations because of adverse events, were low and similar across treatment groups. In the placebo group, 24.4% of subjects reported adverse events compared with 24.1% for fexofenadine HCl 30 mg b.i.d., and 28.4% for all fexofenadine-treated groups. The most common adverse event overall was headache (4.3% placebo; 5.8% fexofenadine HCl 30 mg b.i.d.; and 7.2% any fexofenadine doses). Treatment-related adverse events were similar across treatment groups with no sedative effects. Fexofenadine HCl 30 mg b.i.d. was significantly superior to placebo in reducing the total symptom score and all individual seasonal allergic rhinitis symptoms, including nasal congestion (p < 0.05). Fexofenadine, at doses of up to 60 mg b.i.d., is safe and non-sedating, and fexofenadine HCl 30 mg b.i.d. effectively reduces all seasonal allergic rhinitis symptoms in children aged 6-11 years.
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Rhinoscleroma is a chronic granulomatous infectious disease that is rare in Western Europe. We report the case of a 5-year-old Portuguese boy diagnosed with rhinoscleroma in the context of recurrent epistaxis. He had a 6-month course of antibiotic (amoxicillin plus clavulanate) therapy with full recovery.
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As the relative burden of community-acquired bacterial pneumonia among HIV-positive patients increases, adequate prediction of case severity on presentation is crucial. We sought to determine what characteristics measurable on presentation are predictive of worse outcomes. We studied all admissions for community-acquired bacterial pneumonia over one year at a tertiary centre. Patient demographics, comorbidities, HIV-specific markers and CURB-65 scores on Emergency Department presentation were reviewed. Outcomes of interest included mortality, bacteraemia, intensive care unit admission and orotracheal intubation. A total of 396 patients were included: 49 HIV-positive and 347 HIV-negative. Mean CURB-65 score was 1.3 for HIV-positive and 2.2 for HIV-negative patients (p < 0.0001), its predictive value for mortality being maintained in both groups (p = 0.03 and p < 0.001, respectively). Adjusting for CURB-65 scores, HIV infection by itself was only associated with bacteraemia (adjusted odds ratio [AOR] 7.1, 95% CI [2.6-19.5]). Patients with < 200 CD4 cells/µL presented similar CURB-65 adjusted mortality (aOR 1.7, 95% CI [0.2-15.2]), but higher risk of intensive care unit admission (aOR 5.7, 95% CI [1.5-22.0]) and orotracheal intubation (aOR 9.1, 95% CI [2.2-37.1]), compared to HIV-negative patients. These two associations were not observed in the > 200 CD4 cells/µL subgroup (aOR 2.2, 95% CI [0.7-7.6] and aOR 0.8, 95% CI [0.1-6.5], respectively). Antiretroviral therapy and viral load suppression were not associated with different outcomes (p > 0.05). High CURB-65 scores and CD4 counts < 200 cells/µL were both associated with worse outcomes. Severity assessment scales and CD4 counts may both be helpful in predicting severity in HIV-positive patients presenting with community-acquired bacterial pneumonia.
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Contact dermatitis is a common inflammatory skin condition characterized by erythematous and pruritic skin lesions that occur after contact with a foreign substance. There are two forms of contact dermatitis: irritant and allergic. Irritant contact dermatitis is caused by the non–immune-modulated irritation of the skin by a substance, leading to skin changes. Allergic contact dermatitis is a delayed hypersensitivity reaction in which a foreign substance comes into contact with the skin; skin changes occur after reexposure to the substance. A medical condition referred to as “shoe dermatitis” is a form of contact dermatitis caused by the contact of the foot with parts of the shoe due to these materials. Shoe dermatitis is a diagnostic and therapeutic challenge and is a common type of contact dermatitis. It is imperative the foot and ankle physician become familiar with recognizing signs and symptoms of shoe dermatitis so that their patients can be accurately diagnosis and appropriately treated to avoid secondary infections and disability. This review will first present causative factors for the etiology of shoe contact dermatitis supported by clinical-based evidence as found in the medical literature. Secondly, a description of the signs and symptoms of shoe contact dermatitis will be presented in a narrative fashion. Finally, both treatment options and preventative measures to avoid shoe.
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Background: Non-steroid anti-inflammatory drugs (NSAIDs) are a widely used therapeutic group in the world, and particularly in the Portuguese population. Objective: To compare NSAID’s use by prescription and self-medication acquisition and to determine the pattern of indication of NSAIDs, their usage profile and possible implications for patients’ safety. Methods: A cross-sectional design was used where individuals presenting at a community pharmacy requesting NSAIDs during the study period (one month) were invited to answer a face-to-face interview where socio-demographic characteristics, the indication pattern and previous experience of side effects were assessed. A follow-up interview was performed one week later to assess the incidence of adverse effects. The study was ethically approved. Results: A sample of 130 NSAIDs users was recruited, comprising mostly women (n=87; 66.9%), actively employed (n=77; 59.2%) and presenting a mean age of 49.5 years old (SD=20.49). An equal proportion of individuals acquired NSAIDs by self-medication and with medical prescription (n=65; 50%). Over 4/5 of patients (n=57; 87.7%) acquiring NSAIDs without a prescription were self-medicated by their own initiative, and only 10.8% (n=7) had been advised by the pharmacist. The most commonly acquired active substances were ibuprofen and diclofenac. Self-medicated users more frequently resorted to topical NSAIDs following short term treatments. The major underlying condition motivating NSAIDs sought were musculoskeletal disorders (45.0%), regardless of the regimen. An important proportion of prevalent users of NSAIDs reported previous experience of adverse effects (11.3%). One week after initiating NSAID therapy, a small proportion of patients reported incidence of adverse effects. Conclusion: Self-medication with NSAIDs is sought for numerous medical conditions. Reported adverse effects (prevalent and incident) confirm the need for a more rational use of NSAIDs and ongoing pharmacovigilance.
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Objective: The main objective of this study was to assess the knowledge and attitude among Pharmacy students of the University of Prishtina in regards to the antibiotics. Methods: 144 pharmacy students at the University of Prishtina were recruited in this study to complete a self-administered questionnaire. The total number of questions in this questionnaire was eight (8), covering two (2) major themes: self-report of the current and past antibiotic use and behavior; and anticipated prescription behavior of antibiotics upon graduation. The data was statistically analyzed through using SPSS for Windows. Descriptive analysis was employed, and the results were expressed in frequency and percentages. Results: The results showcased a good knowledge of antibiotic among students. The most common answer of students' knowledge about antibiotics was good or moderate (82 %), while 63.2% of the subjects used antibiotics by self-decision, most of them (45 %) for sore throat. Upon graduation, 56.9 % of the students will not sell antibiotics without prescription and 85.4% think that module for rational use of antibiotics is very necessary to be inside the pharmacy syllabus. Conclusion: The study showed good and moderate knowledge of pharmacy students regarding the antibiotics. Half of them use antibiotics by self-decision but the majority of them stated that they will not serve the antibiotics without medical prescription. Specific modules and training for proper antibiotic use should be implemented within the Pharmacy program in The Faculty of Medicine.
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Spondyloarthropathies (or Spondyloarthritides; SpAs) are a group of heterogeneous but genetically related inflammatory disorders in which ankylosing spondylitis (AS) is considered the prototypic form. Among the genes associated with AS, HLA-B27 allele has the strongest association although the cause is still not clear. Rats transgenic for the human HLA-B27 gene (B27 rats) develop a systemic inflammation mirroring the human SpA symptoms and thus provide a useful model to study the contribution of this MHC class I molecule in the disease development. Of particular interest was the observation of absence of arthritis in B27 rats grown in germ-free conditions and a recent theory suggests that microbial dysbiosis and gut inflammation might play a key role in initiating the HLA-B27-associated diseases. Studies in our laboratory have previously demonstrated that HLA-B27 expression alters the development of the myeloid compartment within the bone marrow (BM) in B27 rat and causes loss of a specific dendritic cell (DC) population involved in self-tolerance mechanisms within the gut. The aim of this thesis was to further analyse the myeloid compartment in B27 rats with a particular focus on the osteoclast progenitors and the bone phenotype and to link this to the gut inflammation. In addition, translational studies analysed peripheral monocyte/pre-osteoclasts in AS patients and teased apart the role of cytokines in in vitro human osteoclast differentiation. To understand the dynamics of the myeloid/monocyte compartment within the B27-associated inflammation, monocytes within the bloodstream and BM of B27 rats were characterised via flow cytometry and their ability to differentiate into osteoclast was assessed in vitro. Moreover, an antibiotic regime was used to reduce the B27 ileitis and to evaluate whether this could affect the migration, the phenotype, and the osteoclastogenic potential of B27 monocytes. B27 animals display a systemic and central increase of “inflammatory” CD43low MOs, which are the main contributors to osteoclastogenesis in vitro. Antibiotic treatment reduced ileitis and also reverted the B27 monocyte phenotype. This was also associated with the reduction of the previous described TNFα-enhancement of osteoclast differentiation from B27 BM precursors. These evidences support the idea that in genetically susceptible individuals inflammation in the gut might influence the myeloid compartment within the BM; in other terms, pre-emptively educate precursor cells to acquire specific phenotype end functions after being recruited into the tissue. This might explain the enhanced differentiation of osteoclast from B27 BM progenitors and thus the HLA-B27-associated bone loss. The data shown in this thesis suggest a link between the immunity within the gut and BM haematopoiesis. This provides an attractive and novel research prospective that could help not only to increase the understanding of the HLA-B27-associated aetiopathogenesis but also to unravel the cellular crosstalk that allows the mucosal immunity to program central cell differentiation. Human translational studies on monocyte subsets, cytokines and cytokine network in AS osteoclastogenesis evidenced altered osteoclast differentiation in the presence of IL-22 although no differences in the phenotype and functions of circulating CD14+ monocytes were observed. In addition, studies on the role of TNFα and TNFRs showed a dual role of this inflammatory cytokine in the human OC differentiation. In particular, the activation of TNFR1 in monocytes in early osteoclastogenesis inhibits OC differentiation while TNFα-biasing for TNFR2 on osteoclast precursors mediates the osteoclastogenic effect. Whether similar mechanisms are involved in the TNFα-mediated joint destruction in human rheumatic diseases needs further investigations. This could contribute to the development of novel and more specific anti-TNFα agents for the treatment of bone erosion. In conclusion, taken together my studies support the idea of a crosstalk between the periphery and the central system during the inflammatory response and provide new insights to the mechanisms behind the enhancement of osteoclastogenesis in B27-associated disorders.
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Naturally-occurring phytochemicals have received a pivotal attention in the last years, due to the increasing evidences of biological activities. Equisetum giganteum L., commonly known as “giant horsetail”, is a native plant from Central and South America, being largely used in dietary supplements as diuretic, hemostatic, antiinflammatory and anti-rheumatic agents [1,2]. The aim of the present study was to evaluate the antioxidant (scavenging effects on 2,2-diphenyl-1-picrylhydrazyl radicals- RSA, reducing power- RP, β-carotene bleaching inhibition- CBI and lipid peroxidation inhibition- LPI), anti-inflammatory (inhibition of NO production in lipopolysaccharidestimulated RAW 264.7 macrophages) and cytotoxic (in a panel of four human tumor cell lines: MCF-7- breast adenocarcinoma, NCI-H460- non-small cell lung cancer, HeLa- cervical carcinoma and HepG2- hepatocellular carcinoma; and in non-tumor porcine liver primary cells- PLP2) properties of E. giganteum, providing a phytochemical characterization of its extract (ethanol/water, 80:20, v/v), by using highperformance liquid chromatography coupled to diode array detection and electrospray ionisation mass spectrometry (HPLC-DAD–ESI/MS). E. giganteum presented fourteen phenolic compounds, two phenolic acids and twelve flavonol glycoside derivatives, mainly kaempferol derivatives, accounting to 81% of the total phenolic content, being kaempferol-O-glucoside-O-rutinoside, the most abundant molecule (7.6 mg/g extract). The extract exhibited antioxidant (EC50 values = 123, 136, 202 and 57.4 μg/mL for RSA, RP, CBI and LPI, respectively), anti-inflammatory (EC50 value = 239 μg/mL) and cytotoxic (GI50 values = 250, 258, 268 and 239 μg/mL for MCF-7, NCI-H460, HeLa and HepG2, respectively) properties, which were positively correlated with its concentration in phenolic compounds. Furthermore, up to 400 μg/mL, it did not revealed toxicity in non-tumor liver cells. Thus, this study highlights the potential of E. giganteum extracts as rich sources of phenolic compounds that can be used in the food, pharmaceutical and cosmetic fields.
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Background: The emergence of multiple-drug resistance bacteria has become a major threat and thus calls for an urgent need to search for new effective and safe anti-bacterial agents. Objectives: This study aims to evaluate the anticancer and antibacterial activities of secondary metabolites from Penicillium sp. , an endophytic fungus associated with leaves of Garcinia nobilis . Methods: The culture filtrate from the fermentation of Penicillium sp. was extracted and analyzed by liquid chromatography– mass spectrometry, and the major metabolites were isolated and identified by spectroscopic analyses and by comparison with published data. The antibacterial activity of the compounds was assessed by broth microdilution method while the anticancer activity was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: The fractionation of the crude extract afforded penialidin A-C (1-3), citromycetin (4), p-hydroxyphenylglyoxalaldoxime (5) and brefelfin A (6). All of the compounds tested here showed antibacterial activity (MIC = 0.50 – 128 μg/mL) against Gramnegative multi-drug resistance bacteria, Vibrio cholerae (causative agent of dreadful disease cholera) and Shigella flexneri (causative agent of shigellosis), as well as the significant anticancer activity (LC50 = 0.88 – 9.21 μg/mL) against HeLa cells. Conclusion: The results obtained indicate that compounds 1-6 showed good antibacterial and anticancer activities with no toxicity to human red blood cells and normal Vero cells.
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Aim: To assess the effect of adding zinc oxide nanoparticles to dental adhesives on their anti-microbial and bond strength properties. Methods: 45 human premolars were cut at the cement enamel junction (CEJ) and the crowns were sliced into buccal and lingual halves. The specimens were classified into three groups, etched with 37% phosphoric acid for 15 s and rinsed for 30 s. Single Bond, Single Bond+5% zinc oxide and Single Bond+10% zinc oxide were used in the first, second and third groups. A cylinder of Z250 composite was bonded and cured for 40 s. For anti-bacterial testing, 10 samples of each group were assessed by direct contact test; 10 μL of bacterial suspension was transferred into tubes containing adhesives and incubated for one hour; 300 μL of brain heart infusion (BHI) broth was added to each tube and after 12 h, 50 μL of bacteria and broth were spread on blood agar plates and incubated for 24 h. Results: The colony count decreased significantly in the second and third groups compared to the first. Conclusions: Incorporation of zinc oxide nanoparticles into dental adhesives increases their anti-microbial properties without affecting their bond strength.
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Purpose: To investigate the phytochemistry and cytotoxic activity of stem bark extracts from Genus dolichocarpa and Duguetia chrysocarpa - two species of the Annonaceae family. Methods: The crude ethanol bark extracts (EtOH) of the plants were obtained by maceration. The crude extracts were suspended in a mixture of methanol (MeOH) and water (H2O) (proportion 3:7 v/v) and partitioned with hexane, chloroform (CHCl3) and ethyl acetate (AcOEt) in ascending order of polarity to obtain the respective fractions. The extracts were evaluated on thin layer chromatography (TLC) plates of silica gel to highlight the main groups of secondary metabolites. Cytotoxicity was tested against human tumor cell lines - OVCAR-8 (ovarian), SF-295 (brain) and HCT-116 (colon) - using 3- (4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Results: The screening results demonstrated that all the extracts were positive for the presence of flavonoids and tannins. The presence of alkaloids also was detected in some extracts. The hexane extract of A. dolichocarpa showed the strongest cytotoxicity against HCT-116 with cell growth inhibition of 89.02 %. Conclusion: The findings demonstrate for the first time the cytotoxic activity of the extracts of A. dolichocarpa and D. chrysocarpa, thus providing some evidence that plants of the Annonaceae family are a source of active secondary metabolites with cytotoxic activity.
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O cancro é a segunda causa de mortalidade a nível mundial. Um dos problemas nos tratamentos atuais de quimioterapia relaciona-se com os efeitos secundários causados pela falta de seletividade dos fármacos utilizados. Assim, um dos desafios atuais é o desenvolvimento de sistemas terapêuticos que permitam potenciar o efeito dos fármacos e diminuir os seus efeitos nocivos. Neste contexto, neste trabalho, foram sintetizados complexos de Fe, Co e Zn com fórmula geral [M(bipy-R)3]x+, a partir dos quais foi possível obter sistemas micelares formados in situ pela adição de um copolímero de PLA-b-PEG ou por introdução de macroligandos poliméricos anfifílicos. Os resultados mostram que as nanopartículas formadas apresentam tamanho e características adequadas para aplicações na terapia dirigida contra o cancro. Os resultados preliminares de citotoxicidade na linha tumoral humana da mama MDAMB231 indicam que todos os compostos estudados apresentam atividade citotóxica relevante, sendo os compostos micelares os mais promissores; Abstract: New micellar transition metals complexes for targeted therapy of cancer Cancer is the second leading cause of mortality worldwide. One problem in the current chemotherapy treatments is related to the severe side effects caused by the lack of selectivity of the drugs in clinical use. Thus, one of the current challenges is the development of new therapeutic systems that allow maximizing the effect of the drugs and reducing their harmful effects. In this context, several Fe, Co and Zn compounds of the general formula [M (bipy-R)3]x+ were synthesized in order to obtain micellar systems, either by in situ addition of a PLA-b-PEG copolymer or by introducing amphiphilic macroligands. The results show that the formed nanoparticles have size and characteristics suitable for applications in targeted therapy against cancer. Preliminary results of cytotoxicity in human breast cancer line MDAMB231 indicate that all the studied compounds show significant cytotoxic activity, being the micellar compounds the most promising agents.
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Lung cancer is an heterogeneous disease, with 1-2% of rare histology. New molecular profiling technologies, such as next generation sequencing (NGS), haverevolutionized the assessment of molecular alteration in clinical practice. We analyzed a cohort of 1408 NSCLC-A patients treated at the Sant'Orsola- Malpighi University Hospital from 2019 to 2021. This analysis was performed using the oncomine focus thermo fischer panel. Of them, 410 (29%) had rare alteration (RET 3%, NTRK 0,2%,FGFR1 2%, MET exon14 skipping 3%, BRAF V600 4%, ALK fusion EGFR exon 20 2%) and 36 (2%)had a uncommon mutation. We enrolled 7 RET- rearranged patients in CRETA and J2G-MC-JZJC clinical trials assessing respectively unselective and selective RET-inhibitors , another 7 patients tested positive for the BRAF V6006 mutation and have been enrolled in the Array clinical trial assessing a novel combination of anti-BRAF and anti-mek agents . Other molecular alterations found are KRAS (Gly12Cys), FGFR1-4 mutation, MET skipping ex14 mutations, respectively eligible for other ongoing open studies such as Amgen 20190009 comparing efficacy of sotorasib vs docetaxel, Fight-207 assessing activity of pemigatinib and CINC280J12201 assessing activity of the novel met inhibitor capmatinib. In 2018 we joined the CHANCE clinical trial,a multicenter study evaluating the efficacy and safety of atezolizumab in patients withrare lung cancer histologies where and 14 patients have been so far enrolled in the Bologna site. Our studies underline the need of tailored approach to NSCLC patients and our results showed that precision medicine is feasible and is an effective approach to cancer treatment.
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β-lactam compounds represent an important class of four-membered cyclic amides (azetidin-2-ones) thanks to their valuable and varied biological activities. The presence of a β-lactam ring in a series of bioactive molecules targeting different proteins, allows us to consider the azetidin-2-one a privileged structure. The constrained four-membered cyclic amide could easily undergo ring-opening reactions by nucleophilic residues in the active sites of enzymes and this is the mechanism suggested for antibacterial activity; moreover, the rigid core structure could favour and actually enhance directional noncovalent bonding for an effective ligand−receptor recognition. Nowadays monocyclic β-lactams are known as anticancer, antidiabetic, anti-tubercular, anti-inflammatory agents and as ligands of integrin receptors. In order to consider different facets of 4-azetidin-2-ones, this theis will be divided into two sections: the first one will be dedicated to the design, synthesis and characterization of biological active β-lactams (new β-lactam based integrin ligands and their different applications and novel N-thio-alkyl substituted azetidinones for the treatment of Tuberculosis); the second one instead, will be based on two projects which consider two different proprieties of β-lactams: stereochemistry, evaluated by biocatalytic methods and reactivity at C-4 position. In the first case we want to obtain enantiomerically pure 4-acetoxy-2-azetidinone, useful for synthesis of stereo-chemically defined bioactive β-lactams, while in the second case we want to study in which conditions the nucleophilic substitutions occur. A final section will be instead dedicated to the research project conducted in Philochem AG, Zurich, under the supervision of Prof. Dario Neri and Dr. Samuele Cazzamalli, based on the study of new cleavable disulfide linkers for small molecule drug conjugates targeting Fibroblast activation protein (FAP).
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Extra cellular vesicles are membrane bound and lipid based nano particles having the size range of 30 to 1000 nm released by a plethora of cells. Their prime function is cellular communication but in the recent studies, the potential of these vesicles to maintain physiological and pathological processes as well as their nano-sized constituents opened doors to its applications in therapeutics, and diagnostics of variety of diseases such as cancer. Their main constituents include lipids, proteins, and RNAs. They are categorized into subtypes such as exosomes, micro-vesicles and apoptotic bodies In recent studies, extracellular vesicles that are derived from plants are gaining high regard due to their variety of advantages such as safety, non-toxicity, and high availability which promotes large scale production. EVs are isolated from mammalian and plant cells using multitude of techniques such as Ultracentrifugation, SEC, Precipitation and so on. Due to the variety in the sources as well as shortcomings arising from the isolation method, a scalable and inexpensive EV isolation method is yet to be designed. This study focusses on isolation of EVs from citrus lemon juice through diafiltration. Lemon is a promising source due to its biological properties to act as antioxidant, anticancer, and anti-inflammatory agents. Lemon derived vesicles was proven to have several proteins analogous to mammalian vesicles. A diafiltration could be carried out for successful removal of impurities and it is a scalable, continuous technique with potentially lower process times. The concentration of purified product and impurities are analysed using Size Exclusion Chromatography in analytical mode. It is also considered imperative to compare the results from diafiltration with gold standard UC. BCA is proposed to evaluate total protein content and DLS for size measurements. Finally, the ideal mode of storage of EVs to protect its internals and its structure is analysed with storage tests.