Cardiovascular diseases represent the principal cause of morbidity and mortality worldwide. It is... more Cardiovascular diseases represent the principal cause of morbidity and mortality worldwide. It is well-known that oxidative stress and inflammatory processes are strongly implicated in their pathogenesis; therefore, anti-oxidant and anti-inflammatory agents can represent effective tools. In recent years a large number of scientific reports have pointed out the nutraceutical and nutritional value of extra virgin olive oils (EVOO), strongholds of the Mediterranean diet, endowed with a high nutritional quality and defined as functional foods. In regard to EVOO, it is a food composed of a major saponifiable fraction, represented by oleic acid, and a minor unsaponifiable fraction, including a high number of vitamins, polyphenols, and squalene. Several reports suggest that the beneficial effects of EVOO are linked to the minor components, but recently, further studies have shed light on the health effects of the fatty fraction and the other constituents of the unsaponifiable fraction. In ...
Since the initial report of nitric oxide (NO) activity, enormous progress has been made over the ... more Since the initial report of nitric oxide (NO) activity, enormous progress has been made over the last two decades in the field of NO research. Whereas most physiological responses triggered by moderate concentrations of NO are mediated by soluble guanylate cyclase activation and the subsequent production of cyclic GMP as the major signaling messenger, recent studies have provided evidence of alternative signaling pathways triggered by high concentrations of NO. These signals operate in part through redox-sensitive regulation of transcription factors, gene expression, transcription, cellular activation, proliferation, and cell death. Numerous results converge to indicate a role for NO in physiological and pathological angiogenesis. Experimental data indicate that NO synthase, depending on the isoforms, the timing, and the degree of activation, may display contradictory effects, expressed during both physiological and pathological angiogenesis. The dual personality of NO will be reviewed in the context of the angiogenesis process.
Global repositories of postmarketing safety reports improve understanding of real-life drug toxic... more Global repositories of postmarketing safety reports improve understanding of real-life drug toxicities, often not observed in clinical trials. The aim of this scoping review was to map the evidence from spontaneous reporting systems studies (SRSs) of antiangiogenic drugs (AADs) in cancer patients and highlight if the found disproportionality signals of adverse events (AEs) were validated and thus mentioned in the respective Summary of product Characteristics (SmPC). This scoping review was conducted according to PRISMA guidelines for scoping reviews. A knowledge gap on the safety of AADs was found: firstly, several cardiovascular AEs were not mentioned in the SmPCs and no pharmacovigilance studies were conducted despite the well-known safety concerns about these drugs on the cardiovascular system. Second, a disproportionality signal (not validated through causality assessment) of pericardial disease was found in the literature for axitinib with no mention in SmPC of the drug. Despit...
IntroductionItalian administrative healthcare databases are frequently used for studies on real-w... more IntroductionItalian administrative healthcare databases are frequently used for studies on real-world drug utilization. However, there is currently a lack of evidence on the accuracy of administrative data in describing the use of infusive antineoplastics. In this study, we used rituximab as a case study to investigate the validity of the regional administrative healthcare database of Tuscany (RAD) in describing the utilization of infusive antineoplastics.MethodsWe identified patients aged 18 years or older who had received ≥1 rituximab administration between 2011 and 2014 in the onco-haematology ward of the University Hospital of Siena. We retrieved this information from the Hospital Pharmacy Database (HPD-UHS) and linked the person-level information to RAD. Patients who had received ≥1dispensing of rituximab, single administration episodes, and patients treated for non-Hodgkin Lymphoma (nHL) or Chronic Lymphocytic Leukemia (CLL) were identified in RAD and validated using HPD-UHS a...
We evaluated the synthesis of nitric oxide (NO) and of the neurotoxic kynurenine metabolites 3OH-... more We evaluated the synthesis of nitric oxide (NO) and of the neurotoxic kynurenine metabolites 3OH-kynurenine and quinolinic acid (QUIN) in interferon-γ (IFN-γ)-activated macrophages of the murine BAC1.2F5 cell line with the aim of investigating the roles of mononuclear phagocytes in inflammatory neurological disorders. IFN-γ induced indoleamine 2,3-dioxygenase (IDO) and NO synthase (NOS) and increased the synthesis of 3OH-kynurenine, QUIN, and NO that accumulated in the incubation medium where they reached neurotoxic levels. Macrophage exposure to norharmane, an IDO inhibitor, resulted in a decreased formation of not only the kynurenine metabolites but also NO. The inhibition of NO synthesis could not be ascribed to reduced NADPH availability or decreased NOS induction. Norharmane inhibited NOS activity also in coronary vascular endothelial cells and in isolated aortic rings. Our findings suggest that activated macrophages release large amounts of neurotoxic molecules and that norhar...
PurposeTo describe the use of hydroxychloroquine (HCQ), azithromycin (AZI) and low‐molecular‐weig... more PurposeTo describe the use of hydroxychloroquine (HCQ), azithromycin (AZI) and low‐molecular‐weight‐heparins (LMWH) by sex among elderly residents in nursing homes (NHs) of Tuscany region (Italy) during the first pandemic peak.MethodsA population‐based drug utilization study was performed linking the Tuscany Administrative Databases (TAD) to the regional COVID‐19 registry. Among elderly patients (≥ 65 years old) registered in TAD on 1st December 2019, new users of HCQ, AZI and LMWH that started the treatment during NHs stay (i.e., no dispensing of the same drug during the previous 6 months) were respectively identified in each month of observation period (December 2019–May 2020). The percentage of subjects diagnosed with COVID‐19 (COVID‐19+) on, or before, the date of first dispensing of the drug of interest was described. Results were stratified by sex (male = M; female = F).ResultsNew users of HCQ, AZI and LMWH were 62, 300, and 1215, respectively. About 95% of HCQ new users recei...
Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of can... more Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide. Many risk factors may increase chance of developing colorectal cancer, in particular some lifestyle-related factors have been linked to colorectal cancer. In fact, the links between diet, weight, and exercise and colorectal cancer risk are some of the strongest for any type of cancer. In particular, natural products derived from foodstuff have assumed a large role in the preventive approach in the treatment of colon cancer. A polyphenol of olive oil, 2-(3, 4-dihydroxyphenil) ethanol (DPE), has been reported to possess scavenging properties, and anti-inflammatory and antithrombotic activities. In this work, we delineate the molecular mechanism by which DPE may inhibit colon cancer progression, interfering with inflammation and angiogenesis. We provide the framework in which compounds possessing antioxidant, antiinflammatory, and antiangiogenic properties might be comb...
We examined the possible cooperation between norepinephrine (NE) and ANG II on proliferation of c... more We examined the possible cooperation between norepinephrine (NE) and ANG II on proliferation of cultured vascular smooth muscle cells (VSMCs) and the involved cellular mechanisms. Nanomolar NE concentrations stimulated VSMC proliferation through a prazosin-sensitive effect. The pretreatment of cells with 100 nM ANG II for 24 h significantly potentiated the NE-induced VSMC proliferation; this potentiating effect of ANG II was blocked by losartan but was unaffected by the AT(2) receptor antagonist PD-123177. ANG II pretreatment also potentiated the increase in inositol phosphate turnover and upregulated the cell expression of fibroblast growth factor (FGF-2) induced by NE. Anti-FGF-2 neutralizing antibodies prevented the potentiating effect of ANG II on NE-induced cell growth. Both ANG II and NE stimulated extracellular signal-related kinase (ERK1) activation, but an ANG II potentiation of the effect of NE on ERK1 activity was not detectable. Moreover, ANG II significantly increased protein synthesis but did not potentiate the hypertrophic effect of NE. These findings demonstrate that ANG II and NE cooperate in promoting VSMC growth and that FGF-2 upregulation is involved in this effect
3484 The levels of nitric oxide (NO) derived from inducible NO synthase (iNOS) and prostaglandin ... more 3484 The levels of nitric oxide (NO) derived from inducible NO synthase (iNOS) and prostaglandin E2 (PGE2) derived from cyclooxygenase-2 (COX-2) correlate with tumor growth, metastasis and angiogenesis. The present study examined the role of iNOS signalling pathway in PGE2-mediated tumor invasiveness and proliferation in A431 cells. Cell invasion and proliferation promoted by PGE2 were completely blocked by iNOS specific silencing RNA (siiNOS) or iNOS-guanylate cyclase (GC) pharmacological inhibition. Consistently, iNOS-GC pathway inhibition also blocked mitogen activated protein kinase-extracellular receptor kinase1-2 (MAPK-ERK1-2) phosphorylation, which was required to mediate PGE2 functions. PGE2 effects were confined to the selective activation of the EP2 receptor subtype. Indeed, EP2-mediated MAPK ERK1-2 activation and cell invasion and proliferation were abolished by the PKA inhibitor H89, as well as by silencing iNOS or by pharmacological inhibiting iNOS-GC pathway. Together,...
Cardiovascular diseases represent the principal cause of morbidity and mortality worldwide. It is... more Cardiovascular diseases represent the principal cause of morbidity and mortality worldwide. It is well-known that oxidative stress and inflammatory processes are strongly implicated in their pathogenesis; therefore, anti-oxidant and anti-inflammatory agents can represent effective tools. In recent years a large number of scientific reports have pointed out the nutraceutical and nutritional value of extra virgin olive oils (EVOO), strongholds of the Mediterranean diet, endowed with a high nutritional quality and defined as functional foods. In regard to EVOO, it is a food composed of a major saponifiable fraction, represented by oleic acid, and a minor unsaponifiable fraction, including a high number of vitamins, polyphenols, and squalene. Several reports suggest that the beneficial effects of EVOO are linked to the minor components, but recently, further studies have shed light on the health effects of the fatty fraction and the other constituents of the unsaponifiable fraction. In ...
Since the initial report of nitric oxide (NO) activity, enormous progress has been made over the ... more Since the initial report of nitric oxide (NO) activity, enormous progress has been made over the last two decades in the field of NO research. Whereas most physiological responses triggered by moderate concentrations of NO are mediated by soluble guanylate cyclase activation and the subsequent production of cyclic GMP as the major signaling messenger, recent studies have provided evidence of alternative signaling pathways triggered by high concentrations of NO. These signals operate in part through redox-sensitive regulation of transcription factors, gene expression, transcription, cellular activation, proliferation, and cell death. Numerous results converge to indicate a role for NO in physiological and pathological angiogenesis. Experimental data indicate that NO synthase, depending on the isoforms, the timing, and the degree of activation, may display contradictory effects, expressed during both physiological and pathological angiogenesis. The dual personality of NO will be reviewed in the context of the angiogenesis process.
Global repositories of postmarketing safety reports improve understanding of real-life drug toxic... more Global repositories of postmarketing safety reports improve understanding of real-life drug toxicities, often not observed in clinical trials. The aim of this scoping review was to map the evidence from spontaneous reporting systems studies (SRSs) of antiangiogenic drugs (AADs) in cancer patients and highlight if the found disproportionality signals of adverse events (AEs) were validated and thus mentioned in the respective Summary of product Characteristics (SmPC). This scoping review was conducted according to PRISMA guidelines for scoping reviews. A knowledge gap on the safety of AADs was found: firstly, several cardiovascular AEs were not mentioned in the SmPCs and no pharmacovigilance studies were conducted despite the well-known safety concerns about these drugs on the cardiovascular system. Second, a disproportionality signal (not validated through causality assessment) of pericardial disease was found in the literature for axitinib with no mention in SmPC of the drug. Despit...
IntroductionItalian administrative healthcare databases are frequently used for studies on real-w... more IntroductionItalian administrative healthcare databases are frequently used for studies on real-world drug utilization. However, there is currently a lack of evidence on the accuracy of administrative data in describing the use of infusive antineoplastics. In this study, we used rituximab as a case study to investigate the validity of the regional administrative healthcare database of Tuscany (RAD) in describing the utilization of infusive antineoplastics.MethodsWe identified patients aged 18 years or older who had received ≥1 rituximab administration between 2011 and 2014 in the onco-haematology ward of the University Hospital of Siena. We retrieved this information from the Hospital Pharmacy Database (HPD-UHS) and linked the person-level information to RAD. Patients who had received ≥1dispensing of rituximab, single administration episodes, and patients treated for non-Hodgkin Lymphoma (nHL) or Chronic Lymphocytic Leukemia (CLL) were identified in RAD and validated using HPD-UHS a...
We evaluated the synthesis of nitric oxide (NO) and of the neurotoxic kynurenine metabolites 3OH-... more We evaluated the synthesis of nitric oxide (NO) and of the neurotoxic kynurenine metabolites 3OH-kynurenine and quinolinic acid (QUIN) in interferon-γ (IFN-γ)-activated macrophages of the murine BAC1.2F5 cell line with the aim of investigating the roles of mononuclear phagocytes in inflammatory neurological disorders. IFN-γ induced indoleamine 2,3-dioxygenase (IDO) and NO synthase (NOS) and increased the synthesis of 3OH-kynurenine, QUIN, and NO that accumulated in the incubation medium where they reached neurotoxic levels. Macrophage exposure to norharmane, an IDO inhibitor, resulted in a decreased formation of not only the kynurenine metabolites but also NO. The inhibition of NO synthesis could not be ascribed to reduced NADPH availability or decreased NOS induction. Norharmane inhibited NOS activity also in coronary vascular endothelial cells and in isolated aortic rings. Our findings suggest that activated macrophages release large amounts of neurotoxic molecules and that norhar...
PurposeTo describe the use of hydroxychloroquine (HCQ), azithromycin (AZI) and low‐molecular‐weig... more PurposeTo describe the use of hydroxychloroquine (HCQ), azithromycin (AZI) and low‐molecular‐weight‐heparins (LMWH) by sex among elderly residents in nursing homes (NHs) of Tuscany region (Italy) during the first pandemic peak.MethodsA population‐based drug utilization study was performed linking the Tuscany Administrative Databases (TAD) to the regional COVID‐19 registry. Among elderly patients (≥ 65 years old) registered in TAD on 1st December 2019, new users of HCQ, AZI and LMWH that started the treatment during NHs stay (i.e., no dispensing of the same drug during the previous 6 months) were respectively identified in each month of observation period (December 2019–May 2020). The percentage of subjects diagnosed with COVID‐19 (COVID‐19+) on, or before, the date of first dispensing of the drug of interest was described. Results were stratified by sex (male = M; female = F).ResultsNew users of HCQ, AZI and LMWH were 62, 300, and 1215, respectively. About 95% of HCQ new users recei...
Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of can... more Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide. Many risk factors may increase chance of developing colorectal cancer, in particular some lifestyle-related factors have been linked to colorectal cancer. In fact, the links between diet, weight, and exercise and colorectal cancer risk are some of the strongest for any type of cancer. In particular, natural products derived from foodstuff have assumed a large role in the preventive approach in the treatment of colon cancer. A polyphenol of olive oil, 2-(3, 4-dihydroxyphenil) ethanol (DPE), has been reported to possess scavenging properties, and anti-inflammatory and antithrombotic activities. In this work, we delineate the molecular mechanism by which DPE may inhibit colon cancer progression, interfering with inflammation and angiogenesis. We provide the framework in which compounds possessing antioxidant, antiinflammatory, and antiangiogenic properties might be comb...
We examined the possible cooperation between norepinephrine (NE) and ANG II on proliferation of c... more We examined the possible cooperation between norepinephrine (NE) and ANG II on proliferation of cultured vascular smooth muscle cells (VSMCs) and the involved cellular mechanisms. Nanomolar NE concentrations stimulated VSMC proliferation through a prazosin-sensitive effect. The pretreatment of cells with 100 nM ANG II for 24 h significantly potentiated the NE-induced VSMC proliferation; this potentiating effect of ANG II was blocked by losartan but was unaffected by the AT(2) receptor antagonist PD-123177. ANG II pretreatment also potentiated the increase in inositol phosphate turnover and upregulated the cell expression of fibroblast growth factor (FGF-2) induced by NE. Anti-FGF-2 neutralizing antibodies prevented the potentiating effect of ANG II on NE-induced cell growth. Both ANG II and NE stimulated extracellular signal-related kinase (ERK1) activation, but an ANG II potentiation of the effect of NE on ERK1 activity was not detectable. Moreover, ANG II significantly increased protein synthesis but did not potentiate the hypertrophic effect of NE. These findings demonstrate that ANG II and NE cooperate in promoting VSMC growth and that FGF-2 upregulation is involved in this effect
3484 The levels of nitric oxide (NO) derived from inducible NO synthase (iNOS) and prostaglandin ... more 3484 The levels of nitric oxide (NO) derived from inducible NO synthase (iNOS) and prostaglandin E2 (PGE2) derived from cyclooxygenase-2 (COX-2) correlate with tumor growth, metastasis and angiogenesis. The present study examined the role of iNOS signalling pathway in PGE2-mediated tumor invasiveness and proliferation in A431 cells. Cell invasion and proliferation promoted by PGE2 were completely blocked by iNOS specific silencing RNA (siiNOS) or iNOS-guanylate cyclase (GC) pharmacological inhibition. Consistently, iNOS-GC pathway inhibition also blocked mitogen activated protein kinase-extracellular receptor kinase1-2 (MAPK-ERK1-2) phosphorylation, which was required to mediate PGE2 functions. PGE2 effects were confined to the selective activation of the EP2 receptor subtype. Indeed, EP2-mediated MAPK ERK1-2 activation and cell invasion and proliferation were abolished by the PKA inhibitor H89, as well as by silencing iNOS or by pharmacological inhibiting iNOS-GC pathway. Together,...
International Journal of Environmental Research and Public Health, 2021
Routinely collected electronic healthcare data (rcEHD) have a tremendous potential for enriching ... more Routinely collected electronic healthcare data (rcEHD) have a tremendous potential for enriching pre-marketing evidence on target- and immunotherapies used to treat lung cancer (LC). A scoping review was performed to provide a structured overview of available rcEHD-based studies on this topic and to support the execution of future research by facilitating access to pertinent literature both for study design and benchmarking. Eligible studies published between 2016 and 2020 in PubMed and ISI Web of Science were searched. Data source and study characteristics, as well as evidence on drug utilization and survival were extracted. Thirty-two studies were included. Twenty-six studies used North American data, while three used European data only. Thirteen studies linked ≥1 data source types among administrative/claims data, cancer registries and medical/health records. Twenty-nine studies retrieved cancer-related information from medical records/cancer registries and 31 studies retrieved information on drug utilization or survival from medical records or administrative/claim data. Most part of studies concerned non-small-cell-LC patients (29 out of 32) while none focused on small-cell-LC. Study cohorts ranged between 85 to 81,983 patients. Only two studies described first-line utilization of immunotherapies. Results from this review will serve as a starting point for the execution of future rcEHD-based studies on innovative LC pharmacotherapies.
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Papers by Sandra Donnini