Publications by authors named "Amelia Filippelli"

74 Publications

Chemical risk in hospital settings: Overview on monitoring strategies and international regulatory aspects.

J Public Health Res 2021 Mar 24;10(1). Epub 2021 Mar 24.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Baronissi (SA).

Chemical risk in hospital settings is a growing concern that health professionals and supervisory authorities must deal with daily. Exposure to chemical risk is quite different depending on the hospital department involved and might origin from multiple sources, such as the use of sterilizing agents, disinfectants, detergents, solvents, heavy metals, dangerous drugs, and anesthetic gases. Improving prevention procedures and constantly monitoring the presence and level of potentially toxic substances, both in workers (biological monitoring) and in working environments (environmental monitoring), might significantly reduce the risk of exposure and contaminations. The purpose of this article is to present an overview on this subject, which includes the current international regulations, the chemical pollutants to which medical and paramedical personnel are mainly exposed, and the strategies developed to improve safety conditions for all healthcare workers.
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http://dx.doi.org/10.4081/jphr.2021.1993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018262PMC
March 2021

Environmental and biological monitoring of formaldehyde inside a hospital setting: a combined approach to manage chemical risk in workplaces.

J Public Health Res 2021 Mar 10;10(1). Epub 2021 Mar 10.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Baronissi .

Background: The safety of healthcare workers exposed to formaldehyde remains a great matter of concern for healthcare management units. This work aimed at describing the results of a combined monitoring approach (environmental and biological) to manage occupational exposure to formaldehyde in a hospital setting.

Design And Methods: Environmental monitoring of working spaces and biological monitoring of urinary formaldehyde in 16 exposed healthcare workers of the Anatomic Pathology Unit of a University Hospital in Southern Italy was performed on a four-year timescale (2016-2019).

Results: Values of aero-dispersed formaldehyde identified were on average low; although workers' urinary formaldehyde levels were also minimal, the statistical analysis highlighted a slight weekly accumulation.

Conclusions: Our data confirm that both environmental and biological monitoring are important to identify risk situations, in particular when values of hazardous compounds are below the accepted occupational exposure levels.
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http://dx.doi.org/10.4081/jphr.2021.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967491PMC
March 2021

Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters.

Pharmaceuticals (Basel) 2021 Mar 1;14(3). Epub 2021 Mar 1.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy.

Pharmacogenomics can identify polymorphisms in genes involved in drug pharmacokinetics and pharmacodynamics determining differences in efficacy and safety and causing inter-individual variability in drug response. Therefore, pharmacogenomics can help clinicians in optimizing therapy based on patient's genotype, also in psychiatric and neurological settings. However, pharmacogenetic screenings for psychotropic drugs are not routinely employed in diagnosis and monitoring of patients treated with mood stabilizers, such as carbamazepine and valproate, because their benefit in clinical practice is still controversial. In this review, we summarize the current knowledge on pharmacogenetic biomarkers of these anticonvulsant drugs.
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http://dx.doi.org/10.3390/ph14030204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001195PMC
March 2021

Regulation of Inflammation and Oxidative Stress by Formyl Peptide Receptors in Cardiovascular Disease Progression.

Life (Basel) 2021 Mar 15;11(3). Epub 2021 Mar 15.

Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.

G protein-coupled receptors (GPCRs) are the most important regulators of cardiac function and are commonly targeted for medical therapeutics. Formyl-Peptide Receptors (FPRs) are members of the GPCR superfamily and play an emerging role in cardiovascular pathologies. FPRs can modulate oxidative stress through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production whose dysregulation has been observed in different cardiovascular diseases. Therefore, many studies are focused on identifying molecular mechanisms of the regulation of ROS production. FPR1, FPR2 and FPR3 belong to the FPRs family and their stimulation triggers phosphorylation of intracellular signaling molecules and nonsignaling proteins that are required for NADPH oxidase activation. Some FPR agonists trigger inflammatory processes, while other ligands activate proresolving or anti-inflammatory pathways, depending on the nature of the ligands. In general, bacterial and mitochondrial formylated peptides activate a proinflammatory cell response through FPR1, while Annexin A1 and Lipoxin A4 are anti-inflammatory FPR2 ligands. FPR2 can also trigger a proinflammatory pathway and the switch between FPR2-mediated pro- and anti-inflammatory cell responses depends on conformational changes of the receptor upon ligand binding. Here we describe the detrimental or beneficial effects of the main FPR agonists and their potential role as new therapeutic and diagnostic targets in the progression of cardiovascular diseases.
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http://dx.doi.org/10.3390/life11030243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998928PMC
March 2021

Molecules and Mechanisms to Overcome Oxidative Stress Inducing Cardiovascular Disease in Cancer Patients.

Life (Basel) 2021 Jan 30;11(2). Epub 2021 Jan 30.

Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, 84081 Baronissi, Italy.

Reactive oxygen species (ROS) are molecules involved in signal transduction pathways with both beneficial and detrimental effects on human cells. ROS are generated by many cellular processes including mitochondrial respiration, metabolism and enzymatic activities. In physiological conditions, ROS levels are well-balanced by antioxidative detoxification systems. In contrast, in pathological conditions such as cardiovascular, neurological and cancer diseases, ROS production exceeds the antioxidative detoxification capacity of cells, leading to cellular damages and death. In this review, we will first describe the biology and mechanisms of ROS mediated oxidative stress in cardiovascular disease. Second, we will review the role of oxidative stress mediated by oncological treatments in inducing cardiovascular disease. Lastly, we will discuss the strategies that potentially counteract the oxidative stress in order to fight the onset and progression of cardiovascular disease, including that induced by oncological treatments.
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http://dx.doi.org/10.3390/life11020105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911715PMC
January 2021

Experimental Pharmacotherapy for COVID-19: The Latest Advances.

J Exp Pharmacol 2021 7;13:1-13. Epub 2021 Jan 7.

Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", Unit of Pharmacology, University of Salerno, Baronissi, Italy.

The coronavirus infectious disease-2019 (COVID-19) has overwhelmed like a shock wave in a completely unprepared world. Despite coronavirus infections were involved in previous epidemic outbreaks, no antiviral agent was developed for specific treatment. As a consequence, since the beginning of this pandemic, both repositioned and experimental drugs were used to treat the infected patients without evidence of clinical efficacy. Just based on experience coming from the use of antiviral agents to treat other viruses (eg, lopinavir/ritonavir, remdesivir) and supposed antiviral or immunomodulatory activities of drugs with no approved antiviral indications (eg hydroxychloroquine, tocilizumab), clinicians have faced the ongoing pandemic. Currently, after about 9 months from the COVID-19 spread, there is still no antiviral agent capable of ensuring the cure of this syndrome. Clinical trials are beginning to confirm the benefits of some drugs, while for other compounds, efficacy and safety have not yet been confirmed. Randomized clinical trials (RCT) have denied or downsized the beneficial effects attributed to certain molecules, such as aminoquinolines, largely used in clinical practice at the beginning of COVID-19 spread. Conversely, at the same time, they have provided evidence for unexpected effectiveness of other agents that have been underutilized, such as steroids, which were not used in SARS treatment because of the threatened effect on viral replication. Evidence deriving from pathologic studies have demonstrated that the prothrombotic effects of SARS-CoV-2 can be prevented by heparin prophylaxis, underlining the need for personalized treatment for patients with severe disease. The main aim of this review is to synthesize the available information and evidence on both repositioned and experimental drugs for the treatment of COVID-19, focusing on the need to exercise caution on the use of unproven medical therapies.
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http://dx.doi.org/10.2147/JEP.S255209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7800714PMC
January 2021

Annexin A1 Released in Extracellular Vesicles by Pancreatic Cancer Cells Activates Components of the Tumor Microenvironment, through Interaction with the Formyl-Peptide Receptors.

Cells 2020 12 18;9(12). Epub 2020 Dec 18.

Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.

Pancreatic cancer (PC) is one of the most aggressive cancers in the world. Several extracellular factors are involved in its development and metastasis to distant organs. In PC, the protein Annexin A1 (ANXA1) appears to be overexpressed and may be identified as an oncogenic factor, also because it is a component in tumor-deriving extracellular vesicles (EVs). Indeed, these microvesicles are known to nourish the tumor microenvironment. Once we evaluated the autocrine role of ANXA1-containing EVs on PC MIA PaCa-2 cells and their pro-angiogenic action, we investigated the ANXA1 paracrine effect on stromal cells like fibroblasts and endothelial ones. Concerning the analysis of fibroblasts, cell migration/invasion, cytoskeleton remodeling, and the different expression of specific protein markers, all features of the cell switching into myofibroblasts, were assessed after administration of wild type more than ANXA1 Knock-Out EVs. Interestingly, we demonstrated a mechanism by which the ANXA1-EVs complex can stimulate the activation of formyl peptide receptors (FPRs), triggering mesenchymal switches and cell motility on both fibroblasts and endothelial cells. Therefore, we highlighted the importance of ANXA1/EVs-FPR axes in PC progression as a vehicle of intercommunication tumor cells-stroma, suggesting a specific potential prognostic/diagnostic role of ANXA1, whether in soluble form or even if EVs are captured in PC.
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http://dx.doi.org/10.3390/cells9122719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767312PMC
December 2020

Case Report: BAP1 Mutation and RAD21 Amplification as Predictive Biomarkers to PARP Inhibitor in Metastatic Intrahepatic Cholangiocarcinoma.

Front Oncol 2020 27;10:567289. Epub 2020 Nov 27.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.

Introduction: Intrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer characterized by a poor prognosis and a limited response to conventional therapies. Currently chemotherapy is the only therapeutic option for patients with Stage IV ICC. Due to the poor response rate, there is an urgent need to identify novel molecular targets to develop novel effective therapies. Precision oncology tests utilizing targeted next-generation sequencing (NGS) platforms have rapidly entered into clinical practice. Profiling the genome and transcriptome of cancer to identify potentially targetable oncogenic pathways may guide the clinical care of the patient.

Case Presentation: We present a 56-year-old male patient affected with metastatic ICC, whose cancer underwent several precision oncology tests by different NGS platforms. A novel BAP1 mutation (splice site c.581-17_585del22) and a RAD21 amplification were identified by a commercial available platform on a metastatic lesion. No germline BAP1 mutations were identified. Several lines of evidences indicate that PARP inhibitor administration might be an effective treatment in presence of BAP1 and/or RAD21 alterations since both BAP1 and RAD21 are involved in the DNA repair pathway, BAP1 interacts with BRCA1 and BRCA1-mediated DNA repair pathway alterations enhance the sensitivity to PARP inhibitor administration. In this case, after failing conventional therapies, patient was treated with PARP inhibitor olaparib. The patient had a partial response according to RECIST criteria with an overall survival of 37.2 months from the time of diagnosis of his ICC. Following 11.0 months on olaparib treatment, sustained stable disease control is ongoing. The patient is still being treated with olaparib and no significant toxicity has been reported.

Conclusion: These findings have clinical relevance since we have shown PARP inhibitor as a potential treatment for ICC patients harboring BAP1 deletion and RAD21 amplification. We have also highlighted the utility of NGS platforms to identify targetable mutations within a cancer.
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http://dx.doi.org/10.3389/fonc.2020.567289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728995PMC
November 2020

Biomarkers to Personalize the Treatment of Rheumatoid Arthritis: Focus on Autoantibodies and Pharmacogenetics.

Biomolecules 2020 12 14;10(12). Epub 2020 Dec 14.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is very complex and heterogeneous. If not adequately treated, RA patients are likely to manifest excess of morbidity and disability with an important impact on the quality of life. Pharmacological treatment is based on the administration of the disease-modifying antirheumatic drugs (DMARDs), subdivided into conventional synthetic (csDMARDs), targeted synthetic (tsDMARDs), and biological (bDMARDs). bDMARDs are now frequently administered in patients, both as alternative treatment and together with csDMARDs. Unfortunately, there is a therapeutic response variability both to old and new drugs. Therefore, to identify pre-therapeutic and on-treatment predictors of response is a priority. This review aims to summarize recent advances in understanding the causes of the variability in treatment response in RA, with particular attention to predictive potential of autoantibodies and DMARD pharmacogenetics. In recent years, several biomarkers have been proposed to personalize the therapy. Unfortunately, a magic bullet does not exist, as many factors concur to disease susceptibility and treatment outcomes, acting around the patient's congenital background. Models integrating demographic, clinical, biochemical, and genetic data are needed to enhance the predictive capacity of specific factors singularly considered to optimize RA treatment in light of multidisciplinary patient management.
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http://dx.doi.org/10.3390/biom10121672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765045PMC
December 2020

Mesoglycan exerts its fibrinolytic effect through the activation of annexin A2.

J Cell Physiol 2021 Jul 7;236(7):4926-4943. Epub 2020 Dec 7.

Department of Pharmacy, University of Salerno, Fisciano (SA), Italy.

Mesoglycan is a drug based on a mixture of glycosaminoglycans mainly used for the treatment of blood vessel diseases acting as antithrombotic and profibrinolytic drugs. Besides the numerous clinical studies, there is no information about its function on the fibrinolytic cascade. Here, we have elucidated the mechanism of action by which mesoglycan induces the activation of plasmin from endothelial cells. Surprisingly, by a proteomic analysis, we found that, following mesoglycan treatment, these cells show a notable amount of annexin A2 (ANXA2) at the plasma membrane. This protein has been widely associated with fibrinolysis and appears able to move to the membrane when phosphorylated. In our model, this translocation has proven to enhance cell migration, invasion, and angiogenesis. Furthermore, the interaction of mesoglycan with syndecan 4 (SDC4), a coreceptor belonging to the class of heparan sulfate proteoglycans, represents the upstream event of the ANXA2 behavior. Indeed, the activation of SDC4 triggers the motility of endothelial cells culminating in angiogenesis. Interestingly, mesoglycan can induce the release of plasmin in endothelial cell supernatants only in the presence of ANXA2. This evaluation suggests that mesoglycan triggers the formation of a chain mechanism starting from the activation of SDC4, and the related cascade of events, including src complex and PKCα activation, promoting the phosphorylation of ANXA2 and its translocation to plasma membrane. This indicates a connection among mesoglycan, SDC4-(PKCα-src), and ANXA2 which, in turn, links the tissue plasminogen activator bringing it closer to plasminogen. This latter is so cleaved to release the plasmin and degrade fibrin sleeves.
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http://dx.doi.org/10.1002/jcp.30207DOI Listing
July 2021

Sirt1 Activity in PBMCs as a Biomarker of Different Heart Failure Phenotypes.

Biomolecules 2020 11 23;10(11). Epub 2020 Nov 23.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy.

Heart Failure (HF) is a syndrome, which implies the existence of different phenotypes. The new categorization includes patients with preserved ejection fraction (HFpEF), mid-range EF (HFmrEF), and reduced EF (HFrEF) but the molecular mechanisms involved in these HF phenotypes have not yet been exhaustively investigated. Sirt1 plays a crucial role in biological processes strongly related to HF. This study aimed to evaluate whether Sirt1 activity was correlated with EF and other parameters in HFpEF, HFmrEF, and HFrEF. Seventy patients, HFpEF ( = 23), HFmrEF ( = 23) and HFrEF ( = 24), were enrolled at the Cardiology Unit of the University Hospital of Salerno. Sirt1 activity was measured in peripheral blood mononuclear cells (PBMCs). Angiotensin-Converting Enzyme 2 (ACE2) activity, Tumor Necrosis Factor-alpha (TNF-α) and Brain Natriuretic Peptide (BNP) levels were quantified in plasma. HFpEF showed lower Sirt1 and ACE2 activities than both HFmrEF and HFrEF ( < 0.0001), without difference compared to No HF controls. In HFmrEF and HFrEF a very strong correlation was found between Sirt1 activity and EF (r = 0.899 and r = 0.909, respectively), and between ACE2 activity and Sirt1 (r = 0.801 and r = 0.802, respectively). HFrEF showed the highest TNF-α levels without reaching statistical significance. Significant differences in BNP were found among the groups, with the highest levels in the HFrEF. Determining Sirt1 activity in PBMCs is useful to distinguish the HF patients' phenotypes from each other, especially HFmrEF/HFrEF from HFpEF.
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http://dx.doi.org/10.3390/biom10111590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700185PMC
November 2020

Effectiveness and Tolerability of a Patch Containing Onion Extract and Allantoin for Cesarean Section Scars.

Front Pharmacol 2020 25;11:569514. Epub 2020 Sep 25.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Baronissi, Italy.

Background: The prevention or early treatment of pathological scars is the most appropriate therapeutic approach. Gels and patches containing onion extract and allantoin are safe and effective in patients with scars of various origins and severity. However, no controlled studies have evaluated the effects of the patch formulation in women after Cesarean delivery. This study aimed to investigate the effects of a patch containing Allium cepa and allantoin on Cesarean section (C-section) scars.

Methods: This is an observational study. Women were consecutively recruited at the University Hospital of Salerno and subdivided into two groups considering the number of C-section. Group A included subjects without and group B with a history of C-section. Scars assessment was made using digital photographs and the Patient and Observer Scar Assessment Scale (POSAS). After 4 weeks, the C-section of the women who had applied a patch containing Allium cepa and allantoin and those of women who had not used any products (controls) were re-evaluated as at baseline. The Observers independently performed the scars assessment at baseline and after 4 weeks. Data are expressed as the difference of the POSAS scores after 4 weeks minus the POSAS scores at baseline. The statistical significance was established at a p value <0.05.

Results: Ninety-three subjects completed the study (47 in group A and 46 in group B). Women who had used a patch showed an improvement in total score by observer scale when compared with controls (p = 0.013). By the patient scale, no significant changes from baseline were found in group A and group B. Group B with patch showed changes in scars' pigmentation (p = 0.015), relief (p = 0.039), and pliability (p = 0.046) in comparison of controls. Digital photographs confirmed such improvements in women who had already undergone previous C-section, while no significant changes from baseline were found in women without a history of C-section.

Conclusions: Intense treatment of just 4 weeks with a patch containing Alium Cepa extract and allantoin was able to improve pigmentation, relief, and pliability of C-section scars in women with a history of C-section.

Clinical Trial Registration: ClinicalTrials.gov, identifier NCT04046783.
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http://dx.doi.org/10.3389/fphar.2020.569514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546780PMC
September 2020

The need of a multicomponent guiding approach to personalize clopidogrel treatment.

Pharmacogenomics J 2021 Apr 9;21(2):116-127. Epub 2020 Oct 9.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno- S, Allende street, 84081, Baronissi, Salerno, Italy.

Patients bearing polymorphisms termed CYP2C19 loss of function (LoF) alleles and ABCB1-C3435T may do not properly respond to standard dosage of clopidogrel and have an increased risk of thrombosis. Moreover, co-administration of proton pump inhibitors (PPIs) and clopidogrel may attenuate the antiplatelet effect. The role of pharmacogenetics and PPIs/clopidogrel drug-drug interaction has been extensively investigated in patients with acute coronary syndrome after stent implantation (ACS/PCI), while data in patients undergoing vascular surgery are scarce. Here we have performed a systematic review to evaluate the available literature in such a clinical setting and have discussed the controversies about the use of CYP2C19 pharmacogenetics and platelet function testing to personalize clopidogrel treatment. In addition, we have made a comparison of the literature data with our findings concerning patients eligible for vascular surgery and treated with clopidogrel, in whom we used a combined management based on the CYP2C19 and ABCB1 pharmacogenetic testing with monitoring of therapeutic adherence and PPIs-clopidogrel interaction. Both our data and those produced during both observational studies and randomized clinical trials confirm the validity of pharmacogenetics to personalize clopidogrel treatment and stress the importance to make a drug monitoring considering all the known variables, potentially responsible for treatment failure. However, the American Heart Association and the European Cardiovascular Society recommend against the routine use of clopidogrel pharmacogenetic testing. An update of the international guidelines on antiplatelet therapy, incorporating the evidence related to CYP2C19 pharmacogenetics and PPIs-clopidogrel drug-drug interactions is warranted both in ACS/PCI patients and subjects undergoing vascular surgery.
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http://dx.doi.org/10.1038/s41397-020-00189-2DOI Listing
April 2021

Misleading meta-analyses of observational studies may generate unjustified alarms: The case of medications for nausea and vomiting in pregnancy.

Pharmacol Res 2021 01 5;163:105229. Epub 2020 Oct 5.

National Centre of Healthcare Research and Pharmacoepidemiology, University of Milano-Bicocca, Milan, Italy; Unit of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy.

Objectives: Because observational studies often use imperfect measurements, results are prone to misclassification errors. We used as a motivating example the possible teratogenic risks of antiemetic agents in pregnancy since a large observational study recently showed that first-trimester exposure to doxylamine-pyridoxine was associated with significantly increased risk of congenital malformations as a whole, as well as central nervous system defects, and previous observational studies did not show such associations. A meta-analysis on this issue was carried out with the aim to illustrate how differential exposure and outcome misclassifications may lead to uncertain conclusions.

Methods: Medline, searched to October 2019 for full text papers in English. Summary Odds Ratios (ORs) with confidence intervals (CIs) were calculated using random-effect models. Probabilistic sensitivity analyses were performed for evaluating the extension of differential misclassification required to account for the exposure-outcome association.

Results: Summary ORs were 1.02 (95 % CI, 0.92-1.15), 0.99 (0.82-1.19) and 1.25 (1.08-1.44) for overall congenital, cardiocirculatory, and central nervous system malformations respectively. By assuming exposure and outcome bias factor respectively of 0.95 (i.e., newborns with congenital defects had exposure specificity 5% lower than healthy newborns) and 1.12 (i.e., exposed newborns had outcome sensitivity 12 % higher than unexposed newborns), summary OR of central nervous system defects became 1.13 (95 % CI, 0.99-1.29) and 1.17 (95 % CI, 0.99-1.38).

Conclusion: Observational investigations and meta-analyses of observational studies need cautious interpretations. Their susceptibility to several, often sneaky, sources of bias should be carefully evaluated.
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http://dx.doi.org/10.1016/j.phrs.2020.105229DOI Listing
January 2021

Heparan sulfate binds the extracellular Annexin A1 and blocks its effects on pancreatic cancer cells.

Biochem Pharmacol 2020 12 28;182:114252. Epub 2020 Sep 28.

Department of Pharmacy, University of Salerno, Fisciano, SA, Italy. Electronic address:

In pancreatic cancer (PC) progression the protein Annexin A1 (ANXA1) has been described as oncogenic factor. Thus, the need to inhibit its action, mainly the extracellular form, has become an appealing cue for the anti-cancer research. Heparan sulfate (HS) is a glycosaminoglycan of the extracellular matrix known to bind several molecules, as growth factors and cytokines, generating a kind of reservoir in the extracellular environment. Here, we started our study by showing the physical calcium-dependent interaction between HS and ANXA1 as both full-length protein and N-terminal portion, Ac2-26 by biophysical techniques. HS is able to inhibit the migration/invasion process of human PC MIA PaCa-2 cells and partially revert their mesenchymal phenotype as reported through the expression of specific protein markers and the growth in colonies and in 3D-spheroids. Furthermore, both on MIA PaCa-2 and PANC-1 cells, HS blocks the effects of Ac2-26, which enhances the aggressive behavior of PC cells if added alone. These effects appear evident also on endothelial cells whose activation is promoted by Ac2-26 but not in presence of HS. Thus, the interference of the interaction ANXA1-HS on angiogenesis strongly emerges. Moreover, once sequestered by HS, ANXA1 is not more able to bind the formil-peptide receptors (FPRs) preventing the increase of calcium mobilization, peculiar for cell motility. These findings introduce a new important tale in the knowledge about the inhibition of the ANXA1 action in PC development. Further information will be useful to highlight the interaction of HS with the protein, focusing on the characterization of the glycosaminoglycan and on in vivo assays.
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http://dx.doi.org/10.1016/j.bcp.2020.114252DOI Listing
December 2020

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature.

J Pers Med 2020 Sep 3;10(3). Epub 2020 Sep 3.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy.

Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the gene. FP pharmacogenetics, including four polymorphisms (-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the -PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the -PGx. We describe a case series of patients in whom we performed -PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of -PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.
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http://dx.doi.org/10.3390/jpm10030113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564232PMC
September 2020

Sex differences in the adherence of antihypertensive drugs: a systematic review with meta-analyses.

BMJ Open 2020 07 8;10(7):e036418. Epub 2020 Jul 8.

Unit of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milano, Italy.

Objectives: Poor worldwide rate of blood pressure control is largely due to poor adherence to antihypertensive (AHT) drug treatment. The question of whether sex affects adherence has long been debated but conflicting findings have been reported on this issue. Our objective was to evaluate sex differences in the adherence to AHT therapy.

Research Design And Methods: Studies were identified through a systematic search of PubMed, CINAHL, PsycINFO, Web of Science and Google Scholar (through January 2020) and manual handsearching of relevant articles. Observational studies reporting adherence to AHT drugs measured by self-report or pharmacy refill prescription-based methods among men and women were included. Summarised estimates of OR with 95% CIs were calculated using random-effects model and meta-regression models.

Results: From 12 849 potentially relevant publications, 82 studies (15 517 457 men and 18 537 599 women) were included. No significant between-sex differences in adherence to AHT were observed, whether all study-specific estimates were summarised (OR 1.04, 95% CI 1.00 to 1.09, p=0.07), nor estimates were pooled according to the method for measuring adherence. Among patients aged 65 years or older, lower self-reported adherence was observed in women (OR 0.84, 95% CI 0.72 to 0.97, p=0.02), while the main result remained unchanged according to other subgroup analyses.

Conclusions: Definitive evidence of sex differences in adherence to AHT therapy cannot be drawn. Our little knowledge about factors affecting adherence, in particular of sex effect among elderly, urgently requires high-quality studies investigating these issues.
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http://dx.doi.org/10.1136/bmjopen-2019-036418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348648PMC
July 2020

Combination of Ruxolitinib and Eculizumab for Treatment of Severe SARS-CoV-2-Related Acute Respiratory Distress Syndrome: A Controlled Study.

Front Pharmacol 2020 5;11:857. Epub 2020 Jun 5.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana" University of Salerno, Baronissi, Italy.

To date, there are no specific therapeutic strategies for treatment of COVID-19. Based on the hypothesis that complement and coagulation cascades are activated by viral infection, and might trigger an acute respiratory distress syndrome (ARDS), we report clinical outcomes of 17 consecutive cases of SARS-CoV-2-related ARDS treated (N = 7) with the novel combination of ruxolitinib, a JAK1/2 inhibitor, 10 mg/twice daily for 14 days and eculizumab, an anti-C5a complement monoclonal antibody, 900 mg IV/weekly for a maximum of three weeks, or with the best available therapy (N = 10). Patients treated with the combination showed significant improvements in respiratory symptoms and radiographic pulmonary lesions and decrease in circulating D-dimer levels compared to the best available therapy group. Our results support the use of combined ruxolitinib and eculizumab for treatment of severe SARS-CoV-2-related ARDS by simultaneously turning off abnormal innate and adaptive immune responses.
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http://dx.doi.org/10.3389/fphar.2020.00857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291857PMC
June 2020

Aptamers and Antisense Oligonucleotides for Diagnosis and Treatment of Hematological Diseases.

Int J Mol Sci 2020 May 4;21(9). Epub 2020 May 4.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Baronissi, 84081 Salerno, Italy.

Aptamers or chemical antibodies are single-stranded DNA or RNA oligonucleotides that bind proteins and small molecules with high affinity and specificity by recognizing tertiary or quaternary structures as antibodies. Aptamers can be easily produced in vitro through a process known as systemic evolution of ligands by exponential enrichment (SELEX) or a cell-based SELEX procedure. Aptamers and modified aptamers, such as slow, off-rate, modified aptamers (SOMAmers), can bind to target molecules with less polar and more hydrophobic interactions showing slower dissociation rates, higher stability, and resistance to nuclease degradation. Aptamers and SOMAmers are largely employed for multiplex high-throughput proteomics analysis with high reproducibility and reliability, for tumor cell detection by flow cytometry or microscopy for research and clinical purposes. In addition, aptamers are increasingly used for novel drug delivery systems specifically targeting tumor cells, and as new anticancer molecules. In this review, we summarize current preclinical and clinical applications of aptamers in malignant and non-malignant hematological diseases.
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http://dx.doi.org/10.3390/ijms21093252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246934PMC
May 2020

Cardioprotective Effects of Dietary Phytochemicals on Oxidative Stress in Heart Failure by a Sex-Gender-Oriented Point of View.

Oxid Med Cell Longev 2020 6;2020:2176728. Epub 2020 Jan 6.

Department of Medicine and Health Sciences, University of Molise, Via Francesco De Sanctis, 1, 86100 Campobasso, Italy.

Dietary phytochemicals are considered an innovative strategy that helps to reduce cardiovascular risk factors. Some phytochemicals have been shown to play a beneficial role in lipid metabolism, to improve endothelial function and to modify oxidative stress pathways in experimental and clinical models of cardiovascular impairment. Importantly, investigation on phytochemical effect on cardiac remodeling appears to be promising. Nowadays, drug therapy and implantation of devices have demonstrated to ameliorate survival. Of interest, sex-gender seems to influence the response to HF canonical therapies. In fact, starting by the evidence of the feminization of world population and the scarce efficacy and safety of the traditional drugs in women, the search of alternative therapeutic tools has become mandatory. The aim of this review is to summarize the possible role of dietary phytochemicals in HF therapy and the evidence of a different sex-gender-oriented response.
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http://dx.doi.org/10.1155/2020/2176728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975222PMC
June 2020

Cardiac Rehabilitation Increases SIRT1 Activity and -Hydroxybutyrate Levels and Decreases Oxidative Stress in Patients with HF with Preserved Ejection Fraction.

Oxid Med Cell Longev 2019 27;2019:7049237. Epub 2019 Nov 27.

Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy.

Purpose: Exercise training induces beneficial effects also by increasing levels of Sirtuin 1 (Sirt1) and -hydroxybutyrate (OHB). Up to date, no studies investigated the role of exercise training-based cardiac rehabilitation (ET-CR) programs on OHB levels. Therefore, the present study is aimed at investigating whether a supervised 4-week ET-CR program was able to induce changes in Sirt1 activity and OHB levels and to evaluate the possible relationship between such parameters, in Heart Failure with preserved Ejection Fraction (HFpEF) patients.

Methods: A prospective longitudinal observational study was conducted on patients consecutively admitted to the Cardiology and Cardiac Rehabilitation Units of "San Gennaro dei Poveri" Hospital in Naples, Italy. In fifty elderly patients affected by HFpEF, in NYHA II and III class, Sirt1 activity, Trolox Equivalent Antioxidant Capacity (TEAC), OHB, and Oxidized Low-Density Lipoprotein (Ox-LDL) levels were measured before and at the end of the ET-CR program. A control group of 20 HFpEF patients was also recruited, and the same parameters were evaluated 4 weeks after the beginning of the study.

Results: ET-CR induced an increase of Sirt1 activity, OHB levels, and antioxidant capacity. Moreover, it was associated with a rise in NAD and NAD/NADH ratio levels and a reduction in Ox-LDL. No changes affected the controls.

Conclusion: The characterization of the ET-CR effects from a metabolic viewpoint might represent an important step to improve the HFpEF management.
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http://dx.doi.org/10.1155/2019/7049237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900956PMC
June 2020

Prospective validation of the International Warfarin Pharmacogenetics Consortium algorithm in high-risk elderly people (VIALE study).

Pharmacogenomics J 2020 06 5;20(3):451-461. Epub 2019 Dec 5.

Department of Mental Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Via L. Armanni 5, 80138, Napoli, Italy.

We assessed the predictive accuracy of the Warfarin Pharmacogenetics Consortium (IWPC) algorithm in a prospective cohort of 376 high-risk elderly patients (≥65 years) who required new treatment with warfarin for either medical (non valvular atrial fibrillation) or surgical conditions (heart valve replacement), had ≥1 comorbid conditions, and regularly used ≥2 other drugs. Follow-up visits were performed according to clinical practice and lasted for a maximum of 1 year. Two hundred and eighty-three (75%) patients achieved a stable maintenance dose. Warfarin maintenance doses were low on average (median 20.3 mg/week, interquartile range, 14.1-27.7 mg/week) and were substantially overestimated by the IWPC algorithm. Overall the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable dose was equal to 37.5%, (95% CI 32.0-43.3%). IWPC algorithm explained only 31% of the actual warfarin dose variability. Modifications of the IWPC algorithm are needed in high-risk elderly people.
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http://dx.doi.org/10.1038/s41397-019-0129-6DOI Listing
June 2020

Novosphingobium sp. PP1Y as a novel source of outer membrane vesicles.

J Microbiol 2019 Jun 27;57(6):498-508. Epub 2019 May 27.

Department of Medicine, Surgery and Dentistry, University of Salerno, Fisciano, Italy.

Outer membrane vesicles (OMVs) are nanostructures of 20-200 nm diameter deriving from the surface of several Gram-negative bacteria. OMVs are emerging as shuttles involved in several mechanisms of communication and environmental adaptation. In this work, OMVs were isolated and characterized from Novosphingobium sp. PP1Y, a Gram-negative non-pathogenic microorganism lacking LPS on the outer membrane surface and whose genome was sequenced and annotated. Scanning electron microscopy performed on samples obtained from a culture in minimal medium highlighted the presence of PP1Y cells embedded in an extracellular matrix rich in vesicular structures. OMVs were collected from the exhausted growth medium during the mid-exponential phase, and purified by ultracentrifugation on a sucrose gradient. Atomic force microscopy, dynamic light scattering and nanoparticle tracking analysis showed that purified PP1Y OMVs had a spherical morphology with a diameter of ca. 150 nm and were homogenous in size and shape. Moreover, proteomic and fatty acid analysis of purified OMVs revealed a specific biochemical "fingerprint", suggesting interesting details concerning their biogenesis and physiological role. Moreover, these extracellular nanostructures do not appear to be cytotoxic on HaCaT cell line, thus paving the way to their future use as novel drug delivery systems.
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http://dx.doi.org/10.1007/s12275-019-8483-2DOI Listing
June 2019

Sulphate mineral waters: A medical resource in several disorders.

J Tradit Complement Med 2020 Jul 22;10(4):320-326. Epub 2019 Apr 22.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via S. Allende, 84081, Baronissi, SA, Italy.

Based on their chemical composition, salus per aquam (spa) mineral waters (or medical mineral waters) can be classified as sulphurous, sulphate, bicarbonate etc. Sulphate mineral waters where the predominant element is sulphate anion SO, are frequently used in clinical therapy. In this review, we describe and analyze the current scientific knowledge concerning the therapeutic effect of sulphate mineral waters in the treatment of several disorders. Moreover, we underline how important is to integrate spa treatments with other therapeutic approaches to meet the various needs that can arise during a specific pathological state.
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http://dx.doi.org/10.1016/j.jtcme.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365777PMC
July 2020

Sulphurous mud-bath therapy for treatment of chronic low back pain caused by lumbar spine osteoarthritis.

Intern Emerg Med 2019 01 13;14(1):187-190. Epub 2018 Oct 13.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via S. Allende, 84081, Baronissi, Salerno, Italy.

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http://dx.doi.org/10.1007/s11739-018-1967-yDOI Listing
January 2019

Multidosing Intramuscular Administration of Methotrexate in Interstitial Pregnancy With Very High Levels of β-hCG: A Case Report and Review of the Literature.

Front Endocrinol (Lausanne) 2018 10;9:363. Epub 2018 Jul 10.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Fisciano, Italy.

Ectopic pregnancy (EP) is the implantation of an embryo outside the endometrial cavity of the uterus. Signs and symptoms of EP may arise between the 6th and the 8th week of gestation and include vaginal bleeding, lower abdominal and pelvic pain. Frequently EPs implant in the fallopian tubes. A rare EP is the interstitial pregnancy, a life-threatening condition being responsible for nearly 20% of all deaths caused by EPs. Because of its unique location, the diagnosis is difficult and based on signs and specific criteria together with measuring of serum β-hCG. Usually, EP is treated by surgical approach, which is associated with increased morbidity, decreased fertility and increased likelihood of hysterectomy and uterine rupture in a subsequent pregnancy. Early diagnosis is crucial to life saving and allowing alternative therapeutic interventions such as pharmacological treatments. Methotrexate (MTX) represents the mainstay therapy. There is no standard care for the interstitial pregnancy for what concerns either surgical or pharmacological approaches. We reported a case of a 36-year-old woman admitted to the Hospital of Salerno-Italy with a value of serum β-hCG of 35,993 IU/L. Transvaginal ultrasonography revealed an empty uterine cavity and a mass of 35.7 mm in diameter characterized by a hypoechoic central area. The patient was in stable haemodynamic condition and no haematologic, renal and hepatic impairments were recorded. Despite the high serum β-hCG levels, a pharmacological approach was preferred to a surgical one. The patient was treated with intramuscular administration of MTX in daily dose of 1 mg/Kg alternated with 0.1 mg/kg folinic acid for 5 days. The patient remained hospitalized for 20 days and no side effects were reported. The decrease of the serum β-hCG was monitored and more than 15% reduction was detected between the 4th and the 7th day after the beginning of the treatment. The serum β-hCG became undetectable 35 days after. A multidosing intramuscular administration of MTX was effective and safe even in the presence of very high serum β-hCG levels. Together with similar cases reported in literature, the present results can contribute to improve the decision making in the treatment of the interstitial pregnancy.
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http://dx.doi.org/10.3389/fendo.2018.00363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048239PMC
July 2018

SIRT1 Activity in Peripheral Blood Mononuclear Cells Correlates with Altered Lung Function in Patients with Chronic Obstructive Pulmonary Disease.

Oxid Med Cell Longev 2018 9;2018:9391261. Epub 2018 May 9.

Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi, Italy.

Background: Oxidative stress is a recognized pathogenic mechanism in chronic obstructive pulmonary disease (COPD). Expression of the NAD-dependent deacetylase Sirtuin 1 (SIRT1), an antiaging molecule with a key role in oxidative stress response, has been described as decreased in the lung of COPD patients. No studies so far investigated whether systemic SIRT1 activity was associated to decreased lung function in this disease.

Methods: We measured SIRT1 protein expression and activity in peripheral blood mononuclear cells (PBMCs) and total oxidative status (TOS), total antioxidant capacity (TEAC), and oxidative stress index (TOS/TEAC) in the plasma of 25 COPD patients, 20 healthy nonsmokers (HnS), and 20 healthy smokers (HS).

Results: The activity of SIRT1 was significantly lower in COPD patients compared to both control groups while protein expression decreased progressively (HnS > HS > COPD). TOS levels were significantly lower in HnS than in smoke-associated subjects (COPD and HS), while TEAC levels were progressively lower according (HnS > HS > COPD). In COPD patients, SIRT1 activity, but not protein levels, correlated significantly with both lung function parameters (FEV1/FVC and FEV1) and TEAC.

Conclusions: These findings suggest loss of SIRT1-driven antioxidant activity as relevant in COPD pathogenesis and identify SIRT1 activity as a potential convenient biomarker for identification of mild/moderate, stable COPD.
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http://dx.doi.org/10.1155/2018/9391261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971245PMC
October 2018

Bleeding events attributable to concurrent use of warfarin and other medications in high-risk elderly: meta-analysis and Italian population-based investigation.

Eur J Clin Pharmacol 2018 Aug 7;74(8):1061-1070. Epub 2018 May 7.

Department of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca, Via Bicocca degli Arcimboldi 8, Edificio U7, Milan, 20126, Italy.

Purpose: The aim of this study was to estimate the proportion of bleedings that occurred among warfarin users attributable to the concomitant use of other medications. A general approach for measuring the impact of the prescriptive inappropriateness on drug adverse outcomes at the population level is described.

Methods: A meta-analysis was conducted to obtain summary relative risks of bleeding associated with concurrent use of warfarin and other medications compared to warfarin use alone. A population-based investigation was performed, in an Italian cohort of cardiopathic patients aged 65 years or older, to estimate the prevalence of concurrent users of warfarin and other medicaments. The population attributable fraction was computed by combining data on summary relative risks and prevalence of concurrent users.

Results: Concomitant use of warfarin and cotrimoxazole, amiodarone, quinolones, macrolides, platelet aggregation inhibitors, SSRIs, NSAIDs, and lipid-lowering agents was associated with an increased risk of bleeding. The corresponding attributable fractions were 3% (95% CI 2 to 4%), 21% (1 to 41%), 21% (17 to 25%), 9% (8 to 10%), 14% (12 to 16%), 6% (5 to 8%), 10% (1 to 20%), and 8% (0 to 18%), respectively.

Conclusions: More than half of bleeding events occurring among frail elderly using warfarin are attributable to a concomitant use of warfarin with certain drugs. Because some of these drugs appear to be essential for the treatment/prevention of cardiovascular conditions, and their concomitant use with warfarin could be acceptable in some cases, proper INR-monitoring and warfarin dose adjustments are requested.
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http://dx.doi.org/10.1007/s00228-018-2467-8DOI Listing
August 2018

Development of a novel ion-pairing HPLC-FL method for the separation and quantification of hydroxychloroquine and its metabolites in whole blood.

Biomed Chromatogr 2018 Aug 16;32(8):e4258. Epub 2018 May 16.

Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi (Salerno), Italy.

Hydroxychloroquine (HCQ) is an old antimalarial drug that has proven to be a safe and effective treatment for systemic lupus erythematosus (SLE) and other autoimmune diseases. Since hematic concentration of HCQ is closely related to the therapeutic response, monitoring the levels of the drug and its metabolites in the blood of HCQ-treated patients helps the clinician in the evaluation of partial or complete unresponsiveness to treatment. We developed and validated a novel ion-pairing HPLC-FL method for the simultaneous dosage of HCQ, and its major metabolites desethylhydroxychloroquine, desethylchloroquine and bisdesethylchloroquine, after extraction from whole blood. This methodological approach was used for the analysis of real samples obtained from patients affected by SLE and undergoing HCQ treatment. The same samples were also analyzed using a previously validated LC/MS/MS method and data obtained with the two approaches were in substantial agreement with each other. Results presented in this work indicate that this approach can be successfully used to monitor the level of HCQ and its metabolites in the blood of various categories of patients (i.e. low and high responders, or those not adhering to the therapy). Comparison of HPLC-FL and LC/MS/MS data confirmed the efficacy of the proposed method for routine clinical analyses.
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http://dx.doi.org/10.1002/bmc.4258DOI Listing
August 2018