Skip to main content

Marco Cosentino

Università degli Studi dell'Insubria, Center for Research in Medical Pharmacology, Faculty Member

Followers

376

Following

105

Co-authors

14

Public Views

Main research interests: pharmacology of neuroimmunomodulation, nervous system-immune system interactions (in particular adrenergic and dopaminergic mechanisms and their clinical relevance in neurological disorders, anti-tumor response, autoimmunity, immune tolerance). Further research interests concern neuro- and immunopharmacology, including the effects of CNS drugs on the immune response and the screening of new candidate drugs for their effects on the nervous system and/or on the immune system.

A specific research area regards the pharmacology of herbs and herbal drugs, in the context of the "PhytoINSURED INTERNATIONAL TRAINING NETWORK - PHYTOceuticals for INnovative & SUstainable REsearch & Drugs" and in collaboration with the Instituto de Investigaciones Biológicas Clemente Estable in Montevideo, Uruguay (www.iibce.edu.uy/).

Clinical interests and research topics:
- Clinical pharmacology (including: applications of pharmacogenetics to individualization of drug therapies, Therapeutic Drug Monitoring, and planning and evaluation of clinical trials of drug therapies);
- Pharmacoepidemiology, with particular regard to the use of drugs as indicators of incidence/prevalence of disease in populations and to the pattern of drug prescriptions as indicators of quality/apppropriateness of therapies;
- Pharmacovigilance, with emphasis on the methodologies for detection and reporting of adverse drug reactions (ADR) in routine medical practice and the factors affecting ADR reporting by medical practitioners.

Additional information:
@University - http://www.uninsubria.eu/research/clinmed/cv_Cosentino.htm
@BioMedExperts - http://www.biomedexperts.com/Profile.bme/1740686/Marco_Cosentino
@ResearcherID - http://www.researcherid.com/rid/A-3848-2010
Address: Center for Research in Medical Pharmacology
University of Insubria
Via Ottorino Rossi n. 9
21100 Varese VA - Italy
Phone (direct): +39 0332 217410/397410
Phone (exchange): +39 0332 217401/397401
Fax: +39 0332 217409/397409

less

Loreta Tauginiene

Kaunas University of Technology

Milan Ojsteršek

Inga Gaizauskaite

Mochammad Tanzil Multazam

Universitas Muhammadiyah Sidoarjo

Shivadas Sivasubramaniam

Nottingham Trent University

Canakkale Onsekiz Mart University

Valentine J Owan

University of Calabar, Calabar, Nigeria.

Marie-Andree Jacob

University of Leeds

InterestsView All (18)

Uploads

Neuroimmune Pharmacology by Marco Cosentino

Repurposing dopaminergic drugs for MS — the evidence mounts

A new study has shown that both in patients with multiple sclerosis (MS) and in healthy controls,... more

Dopaminergic Receptors on CD4+ T Naive and Memory Lymphocytes Correlate with Motor Impairment in Patients with Parkinson's Disease OPEN

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in substantia nigra par... more Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in substantia nigra pars compacta, α-synuclein (α-syn)-rich intraneuronal inclusions (Lewy bodies), and microglial activation. Emerging evidence suggests that CD4+ T lymphocytes contribute to neuroinflammation in PD. Since the mainstay of PD treatment is dopaminergic substitution therapy and dopamine is an established transmitter connecting nervous and immune systems, we examined CD4+ T naive and memory lymphocytes in PD patients and in healthy subjects (HS), with specific regard to dopaminergic receptor (DR) expression. In addition, the in vitro effects of α-syn were assessed on CD4+ T naive and memory cells. Results showed extensive association between DR expression in T lymphocytes and motor dysfunction, as assessed by UPDRS Part III score. In total and CD4+ T naive cells expression of D 1-like DR decrease, while in T memory cells D 2-like DR increase with increasing score. In vitro, α-syn increased CD4+ T memory cells, possibly to a different extent in PD patients and in HS, and affected DR expression with cell subset-specific patterns. The present results support the involvement of peripheral adaptive immunity in PD, and may contribute to develop novel immunotherapies for PD, as well as to better use of current dopaminergic antiparkinson drugs. Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting an estimated 7 to 10 million people worldwide and resulting in both motor and cognitive disturbances 1–3. The main neuropatho-logical features of PD are the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, the appearance of intraneuronal inclusions called Lewy bodies, and the occurrence of microglial activation. Microglial cells in particular are key players in neuroinflammation and neurodegeneration, and peripheral adap-tive immunity has been recently proposed as a major determinant in the regulation of microglial function during neurodegenerative disease 4–7. Over the last 15 years, several studies described the occurrence of peculiar modifications of peripheral immunity in PD, such as decreased CD4+ /CD8+ T-cell ratios, fewer CD4+ CD25+ T cells and increased ratios of interferon (IFN)-γ-producing to interleukin (IL)-4-producing T cells 8 , as well as decreased CD4+ T lympho-cytes and CD19+ B cells 9,10. Both CD8+ and CD4+ T cells (but not B cells) were identified in the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, and evidence obtained in the animal model pointed to CD4+ T cells as main determinants of T cell-mediated dopaminergic cell death 11. Remarkably, Saunders et al. 12 recently reported that PD patients have increased effector/memory CD4+ T cells and decreased CD31+ and α 4β 7+ CD4+ T cells, which are associated with progressive motor dysfunction, suggesting a direct relationship between chronic immune stimulation and

Adrenergic regulation of innate immunity: a review

Sympathoadrenergic modulation of hematopoiesis: a review of available evidence and of therapeutic perspectives

Adrenergic and dopaminergic modulation of immunity in multiple sclerosis: teaching old drugs new tricks

by Marco Cosentino and Franca Marino

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2013

Multiple sclerosis (MS) is an autoimmune disorder of the CNS characterized by inflammation, demye... more Multiple sclerosis (MS) is an autoimmune disorder of the CNS characterized by inflammation, demyelination and axonal loss. Classical evidence in experimental allergic encephalomyelitis, the animal model of MS, support the relevance of sympatoadrenergic as well as of dopaminergic mechanisms. In MS patients, dysregulation of adrenergic and dopaminergic pathways contribute to the disease in immune system cells as well as in glial cells. Available evidence is summarized and discussed also in the light of the novel role of dopamine, noradrenaline and adrenaline as transmitters in immune cells, providing a conceptual frame to exploit the potential of several dopaminergic and adrenergic agents, already in clinical use for non-immune indications and with a usually favourable risk-benefit profile, as add-on drugs to conventional immunomodulating therapies in MS.

Adrenergic modulation of immune cells: an update

Amino acids, 2013

Sympathoadrenergic pathways are crucial to the communication between the nervous system and the i... more Sympathoadrenergic pathways are crucial to the communication between the nervous system and the immune system. The present review addresses emerging issues in the adrenergic modulation of immune cells, including: the specific pattern of adrenoceptor expression on immune cells and their role and changes upon cell differentiation and activation; the production and utilization of noradrenaline and adrenaline by immune cells themselves; the dysregulation of adrenergic immune mechanisms in disease and their potential as novel therapeutic targets. A wide array of sympathoadrenergic therapeutics is currently used for non-immune indications, and could represent an attractive source of non-conventional immunomodulating agents.

Expression of Dopaminergic Receptors on Human CD4+ T Lymphocytes: Flow Cytometric Analysis of Naive and Memory Subsets and Relevance for the Neuroimmunology of Neurodegenerative Disease

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2014

Dopamine (DA) is a crucial transmitter in the neuroimmune network, where it contributes to the ne... more Dopamine (DA) is a crucial transmitter in the neuroimmune network, where it contributes to the nervous system-immune system interplay as well as in the communication among immune cells. DA acts through five different dopaminergic receptors (DR) grouped into two families: the D1-like (D1 and D5) and the D2-like (D2, D3 and D4). By use of 5-color flow cytometric analysis, we examined the expression of DR on human CD4+ naive T lymphocytes (CD3+CD4+CD45RA+CCR7+), central memory (TCM, CD3+CD4+CD45RA-CCR7+) and effector memory T cells (TEM, CD3+CD4+CD45RA-CCR7-). In addition, in cultured CD4+ T cells we investigated the changes in DR expression induced by stimulation with antiCD3/antiCD28 antibodies. Results showed that CD4+ T cells always expressed all the five DR: D1-like DR were identified on average on 11.6–13.1 % and D2-like DR on 3.1–8.1 % of the cells. DR on CD4+ naive T cells, TCM, and TEM had distinct expression patterns: naive T cells expressed more D1-like than D2-like DR, which on the contrary were increased in TCM and TEM cells. In cultured CD4+ T cells stimulation with anti-CD3/anti-CD28 antibodies increased the expression of D1-like DR by 71–84 % and of D2-like DR by 55–97 %. The frequency of DR was higher in apoptotic cells in comparison to viable cells, however stimulation increased all DR on viable cells, without affecting their expression on apoptotic cells. The present results contribute to unravel the complexity of dopaminergic pathways in human CD4+ T lymphocytes, suggesting their involvement in memory functions as well as in apoptotic processes. In view of the role of CD4+ memory T cells in neuroinflammation and neurodegeneration during Parkinson’s disease, the relevance of these findings must be assessed in the clinical setting.

Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop

by Franca Marino and Marco Cosentino

Blood, 2007

CD4 ؉ CD25 ؉ regulatory T lymphocytes (Tregs) are specialized T cells playing a key role in the c... more CD4 ؉ CD25 ؉ regulatory T lymphocytes (Tregs) are specialized T cells playing a key role in the control of immune homeostasis. Here, we show that human Tregs constitutively express tyrosine hydroxylase (TH, EC 1.14.16.2), the rate-limiting enzyme in the synthesis of catecholamines, and contain substantial amounts of dopamine, norepinephrine, and epinephrine, which are released upon treatment with reserpine. Catecholamine release results in reduced production of interleukin-10 and transform-ing growth factor-␤ by Tregs, and in downregulation of Treg-dependent inhibition of effector T-lymphocyte (Teff) proliferation, which occurs without affecting the production of tumor necrosis factor-␣ or inter-

Catecholamine production and tyrosine hydroxylase expression in peripheral blood mononuclear cells from multiple sclerosis patients: effect of cell stimulation and possible relevance for activation-induced apoptosis

Journal of Neuroimmunology, 2002

Sympathoadrenergic mechanisms may play a role in multiple sclerosis (MS). We examined catecholami... more Sympathoadrenergic mechanisms may play a role in multiple sclerosis (MS). We examined catecholamine (CA) levels and production and tyrosine hydroxylase (TH) expression in peripheral blood mononuclear cells (PBMCs) from MS patients, and the correlation between CA production and apoptosis in PBMCs. PBMCs from MS patients had increased norepinephrine (NE) levels. However, phytohaemagglutinin (PHA)-stimulated PBMCs from MS patients with active disease synthesized less dopamine (DA) than cells from both healthy controls and patients with inactive disease. PBMCs from patients with inactive disease showed lower expression of TH. Pharmacological inhibition of TH in cultured PBMCs stimulated with PHA reduced the percentage of apoptotic cells. Since a failure of activation-induced apoptosis in immune cells may be involved in MS, it is suggested that altered CA production by PBMCs may be implicated in such dysregulation. D

Endogenous catecholamine synthesis, metabolism, storage, and uptake in human peripheral blood mononuclear cells

Experimental Hematology, 1999

Evidence has been obtained that peripheral blood mononuclear cells contain dopamine, norepinephri... more Evidence has been obtained that peripheral blood mononuclear cells contain dopamine, norepinephrine, epinephrine, and their metabolites. Pharmacologic inhibition of tyrosine hydroxylase or monoamine oxidase profoundly affected intracellular catecholamines (CTs) and their metabolites, indicating that these cells are able to synthesize and breakdown CTs. The sensitivity of intracellular CTs to reserpine and the presence of CTs in the extracellular medium suggest that CTs are stored and released. Moreover, the increase of extracellular CTs in the presence of monoamine uptake blockers point to the presence of functional uptake mechanisms. Altogether, these results indicate the existence of a CT lifecycle in human mononuclear cells and warrant further studies to investigate the role of adrenergic autoregulatory mechanisms in modulation of the immune response and in the pathogenesis of diseases involving the immune system.

Neural and endogenous catecholamines in the bone marrow. Circadian association of norepinephrine with hematopoiesis?

Members of our research team have recently reported that adrenergic agents may affect hematopoies... more Members of our research team have recently reported that adrenergic agents may affect hematopoiesis via alpha1-adrenoceptors present on bone marrow B cell precursors. In this paper we demonstrate that murine bone marrow contains a substantial amount of catecholamines. Norepinephrine (NE) and dopamine (DA) exhibited a daily rhythmicity, with peak values observed during the night. The rhythm was disrupted by chemical sympathectomy, whereas epinephrine (E) showed no rhythmicity or sensitivity to 6-hydroxydopamine. High and low values of NE and DA were associated with high and low values of their metabolites, which indicated a rhythmic catecholamine release. NE, but not DA or E, was positively associated with the proportion of cells in the G2/M and S phases of the cell cycle. Moreover, NE and DA were found in both short-term and long-term bone marrow cultures as well as in human or murine B lymphoid cell lines. These findings indicate that endogenous catecholamines in the bone marrow have both neural and cellular origins. The neural input shows a daily rhythm and may be implicated in the regulation of hematopoiesis.

Catecholamine-producing cells in the synovial tissue during arthritis: modulation of sympathetic neurotransmitters as new therapeutic target

Annals of the rheumatic diseases, 2010

Background The proinfl ammatory and anti-infl ammatory role of the sympathetic nervous system in ... more Background The proinfl ammatory and anti-infl ammatory role of the sympathetic nervous system in early and late infl ammation is an unresolved paradox. A drastic loss of sympathetic nerve fi bres in the synovial tissue of patients with rheumatoid arthritis (RA) has previously been demonstrated. The presence of tyrosine hydroxylase (TH)-positive cells in RA and osteoarthritis (OA) has been determined, but the role of these cells in infl ammation is still unclear.

The first Insubria autumn school on neuroimmunopharmacology: challenging paradigms beyond boundaries

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2013

This issue of the Journal of Neuroimmune Pharmacology is dedicated, in part, to the proceedings o... more This issue of the Journal of Neuroimmune Pharmacology is dedicated, in part, to the proceedings of the First Insubria Autumn School on Neuroimmunopharmacology, organized by Marco Cosentino, Georges J.M. Maestroni, Franca Marino (University of Insubria, Varese, Italy), Manfred Schedlowsky (University of Duisburg-Essen, Germany) and Rainer H. Straub (University of Regensburg, Germany), which took place in November 2011 in Varese, Italy. The School was attended by 50 graduate students and postdoctoral fellows in medical and biological disciplines from 16 european universities and 25 faculties/departments.

Dopaminergic modulation of CD4+CD25(high) regulatory T lymphocytes in multiple sclerosis patients during interferon-β therapy

Neuroimmunomodulation, 2012

paired and DA had no more effect on Treg. In comparison to cells from HCs, Treg from MS patients ... more paired and DA had no more effect on Treg. In comparison to cells from HCs, Treg from MS patients at baseline had increased mRNA for DR D5 and TH (but not for DR D3). During treatment with IFN-␤ , both DR D5 and TH mRNA decreased down to values lower than those of cells from HCs. In comparison to HCs, MS patients had a higher frequency of circulating Treg, both at baseline and after IFN-␤ , while FoxP3 mRNA levels in Treg were similar in patients and HCs and did not show major changes during IFN-␤ . Conclusions: Dopaminergic inhibition of Treg in MS patients is suppressed during IFN-␤ treatment. Treg play a key role in the suppression of autoimmunity, thus the effect may have a therapeutic repercussion.

Expression of apoptosis-related proteins and of mRNA for dopaminergic receptors in peripheral blood mononuclear cells from patients with Alzheimer disease

Alzheimer disease and associated disorders

In search for biomarkers of neurodegeneration, increasing attention has been focussed on peripher... more In search for biomarkers of neurodegeneration, increasing attention has been focussed on peripheral blood mononuclear cells (PBMC). In particular, PBMC from patients with Alzheimer disease (AD) have been suggested to carry apoptotic changes and alterations of neurotransmitter receptor expression, which may resemble those occurring in central nervous system neurons. We investigated the expression of apoptosis-related proteins Bcl-2, Bax, and caspase-3 and the levels of dopaminergic receptors (DR) D3 and D5 mRNA in PBMC from 17 AD patients and 11 age-matched healthy subjects. Apoptosis-related proteins were assayed by standard Western blotting analysis and DR mRNA by real-time polymerase chain reaction techniques. PBMC from healthy subjects and from AD patients expressed Bcl-2, Bax, and caspase-3 to about the same extent, and the Bcl-2/Bax ratio did not differ in the 2 groups. Levels of mRNA for DRD3 and DRD5 were similar in cells from healthy subjects and from AD patients. In conclusion, we found no evidence that PBMC from AD patients may express apoptosis-related proteins or DR mRNA to any different extent in comparison to cells from healthy subjects. These findings do not necessarily imply that immune cells cannot be exploited as biomarkers in AD (and in other central nervous system disorders). Future studies, however, should take into account the inherent complexity of the immune network.

Calcium homeostasis is dysregulated in parkinsonian patients with L-DOPA-induced dyskinesias

Annals of the New York Academy of Sciences, 2003

Long-term treatment of Parkinson disease (PD) is frequently associated with l-3,4-dihydroxyphenyl... more Long-term treatment of Parkinson disease (PD) is frequently associated with l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs). L-DOPA-induced dyskinesias are likely due to changes in the signal transduction pathways, at the striatal level, related to pulsatile stimulation of dopamine receptors. We investigated whether markers of this phenomenon can also be detected peripherally. We analyzed mRNA expression for D5 (D1-like) and D3 (D2-like) receptors and levels of second messengers, such as cAMP and free intracellular Ca2+ ([Ca2+]i), in peripheral blood lymphocytes of PD patients with (LID+) or without LIDs (LID-). Patients with PD showed depressed [Ca2+]i rise in response to mitogen-induced activation. The defect was more pronounced in LID+ (-33% with respect to healthy controls) than in LID- patients (-20%). Peripheral blood lymphocyte levels of cAMP were decreased in both LID+ (3.8 +/- 2.9 pmol/10 cells) and LID- patients (4.2 +/- 2.4 pmol/10(6) cells), with respect to controls (6 +/- 2.6 pmol/10(6) cells). No differences were found in dopamine receptor mRNA expression. Our results demonstrate that second messenger levels are altered in the peripheral blood lymphocytes of PD patients treated with dopaminergic agents and that patients with LIDs show further alterations in the regulation of [Ca2+]i homeostasis. This may represent a distinctive trait of patients prone to develop dyskinetic movements.

Peripheral markers of apoptosis in Parkinson's disease: the effect of dopaminergic drugs

Trends in immunology, 2003

Effects of dopaminergic stimulation on peripheral markers of apoptosis: relevance to Parkinson's disease

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2003

We investigated the effects of dopaminergic stimulation on anti-apoptotic protein Bcl-2, pro-apop... more We investigated the effects of dopaminergic stimulation on anti-apoptotic protein Bcl-2, pro-apoptotic enzyme caspase- 3, and anti-oxidant/anti-apoptotic enzyme Cu/Zn superoxide dismutase (SOD) in human lymphocytes exposed to dopamine (DA). The same determinations were also carried out in parkinsonian patients treated with L-dopa. Caspase-3 activity and Cu/Zn SOD levels tended to increase when lymphocytes were exposed to low or intermediate doses of DA, while a decrease was observed, particularly in caspase-3 activity, with the higher DA dose. Bcl-2 levels were unaffected. In patients, we observed a negative correlation between Cu/Zn SOD levels and daily intake of L-dopa, which also tended to be negatively correlated with caspase-3 activity, but not with Bcl- 2. Our results show that dopaminergic stimulation is associated with complex changes in regulatory proteins of apoptosis.

Unravelling dopamine (and catecholamine) physiopharmacology in lymphocytes: open questions

Trends in immunology, 2003

Evidence for a neuroimmunomodulatory and a hematopoietic role of the Luschka's coccygeal body(3

Neuro endocrinology letters, 2000

OBJECTIVES: In humans the glomus coccygeus was described in 1860 by Luschka. It is present at the... more OBJECTIVES: In humans the glomus coccygeus was described in 1860 by Luschka. It is present at the coccyx tip and corresponds to a complex anastomosis between the median sacral artery and vein, and it is innervated by sympathetic fi bers. In rats and mice it has been located in the tail ventral face. Its function is not known. According to our previous work, which demonstrated that hematopoiesis is under a noradrenergic control and based on the presence of epithelioid cells and sympathetic innervation, we assumed that the coccygeal gland might infl uence hematopoiesis via neuroendocrine or neural mechanisms. Therefore, the present study was undertaken to analyze the effect of glomus coccygeus on hematopoiesis. MATERIAL & METHODS: Peripheral blood leukocyte and platelet concentrations as well as body temperature (BT) and body weight (BW), and norepinephrine (NE), adrenaline (A) and dopamine (DA) content in bone marrow of Luschkaectomized (LCGx), Sham LCGx operated (ShLCGx) and normal mice (Co) were investigated. RESULTS: We found that in LCGx vs. ShLCGx and Co, platelets and neutrophils increased while lymphocytes decreased. The effect of LCGx was signifi cant from day 0 until day 65. Total leukocytes, monocytes, granulocytes, eosinophils and BT did not show any variation. Moreover, 22 days after the operation the amount of NE, A and DA seemed to be decreased in LCGx vs. ShLCGx while the difference was less evident between ShLCGx vs. Co. CONCLUSIONS: This study suggests for the fi rst time a possible hematopoietic function and an immunomodulatory activity of the "Luschka's body" or Coccygeal body by a modulation of the sympathetic nervous system.

Repurposing dopaminergic drugs for MS — the evidence mounts

A new study has shown that both in patients with multiple sclerosis (MS) and in healthy controls,... more

Dopaminergic Receptors on CD4+ T Naive and Memory Lymphocytes Correlate with Motor Impairment in Patients with Parkinson's Disease OPEN

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in substantia nigra par... more Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in substantia nigra pars compacta, α-synuclein (α-syn)-rich intraneuronal inclusions (Lewy bodies), and microglial activation. Emerging evidence suggests that CD4+ T lymphocytes contribute to neuroinflammation in PD. Since the mainstay of PD treatment is dopaminergic substitution therapy and dopamine is an established transmitter connecting nervous and immune systems, we examined CD4+ T naive and memory lymphocytes in PD patients and in healthy subjects (HS), with specific regard to dopaminergic receptor (DR) expression. In addition, the in vitro effects of α-syn were assessed on CD4+ T naive and memory cells. Results showed extensive association between DR expression in T lymphocytes and motor dysfunction, as assessed by UPDRS Part III score. In total and CD4+ T naive cells expression of D 1-like DR decrease, while in T memory cells D 2-like DR increase with increasing score. In vitro, α-syn increased CD4+ T memory cells, possibly to a different extent in PD patients and in HS, and affected DR expression with cell subset-specific patterns. The present results support the involvement of peripheral adaptive immunity in PD, and may contribute to develop novel immunotherapies for PD, as well as to better use of current dopaminergic antiparkinson drugs. Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting an estimated 7 to 10 million people worldwide and resulting in both motor and cognitive disturbances 1–3. The main neuropatho-logical features of PD are the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, the appearance of intraneuronal inclusions called Lewy bodies, and the occurrence of microglial activation. Microglial cells in particular are key players in neuroinflammation and neurodegeneration, and peripheral adap-tive immunity has been recently proposed as a major determinant in the regulation of microglial function during neurodegenerative disease 4–7. Over the last 15 years, several studies described the occurrence of peculiar modifications of peripheral immunity in PD, such as decreased CD4+ /CD8+ T-cell ratios, fewer CD4+ CD25+ T cells and increased ratios of interferon (IFN)-γ-producing to interleukin (IL)-4-producing T cells 8 , as well as decreased CD4+ T lympho-cytes and CD19+ B cells 9,10. Both CD8+ and CD4+ T cells (but not B cells) were identified in the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, and evidence obtained in the animal model pointed to CD4+ T cells as main determinants of T cell-mediated dopaminergic cell death 11. Remarkably, Saunders et al. 12 recently reported that PD patients have increased effector/memory CD4+ T cells and decreased CD31+ and α 4β 7+ CD4+ T cells, which are associated with progressive motor dysfunction, suggesting a direct relationship between chronic immune stimulation and

Adrenergic regulation of innate immunity: a review

Sympathoadrenergic modulation of hematopoiesis: a review of available evidence and of therapeutic perspectives

Adrenergic and dopaminergic modulation of immunity in multiple sclerosis: teaching old drugs new tricks

by Marco Cosentino and Franca Marino

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2013

Multiple sclerosis (MS) is an autoimmune disorder of the CNS characterized by inflammation, demye... more Multiple sclerosis (MS) is an autoimmune disorder of the CNS characterized by inflammation, demyelination and axonal loss. Classical evidence in experimental allergic encephalomyelitis, the animal model of MS, support the relevance of sympatoadrenergic as well as of dopaminergic mechanisms. In MS patients, dysregulation of adrenergic and dopaminergic pathways contribute to the disease in immune system cells as well as in glial cells. Available evidence is summarized and discussed also in the light of the novel role of dopamine, noradrenaline and adrenaline as transmitters in immune cells, providing a conceptual frame to exploit the potential of several dopaminergic and adrenergic agents, already in clinical use for non-immune indications and with a usually favourable risk-benefit profile, as add-on drugs to conventional immunomodulating therapies in MS.

Adrenergic modulation of immune cells: an update

Amino acids, 2013

Sympathoadrenergic pathways are crucial to the communication between the nervous system and the i... more Sympathoadrenergic pathways are crucial to the communication between the nervous system and the immune system. The present review addresses emerging issues in the adrenergic modulation of immune cells, including: the specific pattern of adrenoceptor expression on immune cells and their role and changes upon cell differentiation and activation; the production and utilization of noradrenaline and adrenaline by immune cells themselves; the dysregulation of adrenergic immune mechanisms in disease and their potential as novel therapeutic targets. A wide array of sympathoadrenergic therapeutics is currently used for non-immune indications, and could represent an attractive source of non-conventional immunomodulating agents.

Expression of Dopaminergic Receptors on Human CD4+ T Lymphocytes: Flow Cytometric Analysis of Naive and Memory Subsets and Relevance for the Neuroimmunology of Neurodegenerative Disease

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2014

Dopamine (DA) is a crucial transmitter in the neuroimmune network, where it contributes to the ne... more Dopamine (DA) is a crucial transmitter in the neuroimmune network, where it contributes to the nervous system-immune system interplay as well as in the communication among immune cells. DA acts through five different dopaminergic receptors (DR) grouped into two families: the D1-like (D1 and D5) and the D2-like (D2, D3 and D4). By use of 5-color flow cytometric analysis, we examined the expression of DR on human CD4+ naive T lymphocytes (CD3+CD4+CD45RA+CCR7+), central memory (TCM, CD3+CD4+CD45RA-CCR7+) and effector memory T cells (TEM, CD3+CD4+CD45RA-CCR7-). In addition, in cultured CD4+ T cells we investigated the changes in DR expression induced by stimulation with antiCD3/antiCD28 antibodies. Results showed that CD4+ T cells always expressed all the five DR: D1-like DR were identified on average on 11.6–13.1 % and D2-like DR on 3.1–8.1 % of the cells. DR on CD4+ naive T cells, TCM, and TEM had distinct expression patterns: naive T cells expressed more D1-like than D2-like DR, which on the contrary were increased in TCM and TEM cells. In cultured CD4+ T cells stimulation with anti-CD3/anti-CD28 antibodies increased the expression of D1-like DR by 71–84 % and of D2-like DR by 55–97 %. The frequency of DR was higher in apoptotic cells in comparison to viable cells, however stimulation increased all DR on viable cells, without affecting their expression on apoptotic cells. The present results contribute to unravel the complexity of dopaminergic pathways in human CD4+ T lymphocytes, suggesting their involvement in memory functions as well as in apoptotic processes. In view of the role of CD4+ memory T cells in neuroinflammation and neurodegeneration during Parkinson’s disease, the relevance of these findings must be assessed in the clinical setting.

Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop

by Franca Marino and Marco Cosentino

Blood, 2007

CD4 ؉ CD25 ؉ regulatory T lymphocytes (Tregs) are specialized T cells playing a key role in the c... more CD4 ؉ CD25 ؉ regulatory T lymphocytes (Tregs) are specialized T cells playing a key role in the control of immune homeostasis. Here, we show that human Tregs constitutively express tyrosine hydroxylase (TH, EC 1.14.16.2), the rate-limiting enzyme in the synthesis of catecholamines, and contain substantial amounts of dopamine, norepinephrine, and epinephrine, which are released upon treatment with reserpine. Catecholamine release results in reduced production of interleukin-10 and transform-ing growth factor-␤ by Tregs, and in downregulation of Treg-dependent inhibition of effector T-lymphocyte (Teff) proliferation, which occurs without affecting the production of tumor necrosis factor-␣ or inter-

Catecholamine production and tyrosine hydroxylase expression in peripheral blood mononuclear cells from multiple sclerosis patients: effect of cell stimulation and possible relevance for activation-induced apoptosis

Journal of Neuroimmunology, 2002

Sympathoadrenergic mechanisms may play a role in multiple sclerosis (MS). We examined catecholami... more Sympathoadrenergic mechanisms may play a role in multiple sclerosis (MS). We examined catecholamine (CA) levels and production and tyrosine hydroxylase (TH) expression in peripheral blood mononuclear cells (PBMCs) from MS patients, and the correlation between CA production and apoptosis in PBMCs. PBMCs from MS patients had increased norepinephrine (NE) levels. However, phytohaemagglutinin (PHA)-stimulated PBMCs from MS patients with active disease synthesized less dopamine (DA) than cells from both healthy controls and patients with inactive disease. PBMCs from patients with inactive disease showed lower expression of TH. Pharmacological inhibition of TH in cultured PBMCs stimulated with PHA reduced the percentage of apoptotic cells. Since a failure of activation-induced apoptosis in immune cells may be involved in MS, it is suggested that altered CA production by PBMCs may be implicated in such dysregulation. D

Endogenous catecholamine synthesis, metabolism, storage, and uptake in human peripheral blood mononuclear cells

Experimental Hematology, 1999

Evidence has been obtained that peripheral blood mononuclear cells contain dopamine, norepinephri... more Evidence has been obtained that peripheral blood mononuclear cells contain dopamine, norepinephrine, epinephrine, and their metabolites. Pharmacologic inhibition of tyrosine hydroxylase or monoamine oxidase profoundly affected intracellular catecholamines (CTs) and their metabolites, indicating that these cells are able to synthesize and breakdown CTs. The sensitivity of intracellular CTs to reserpine and the presence of CTs in the extracellular medium suggest that CTs are stored and released. Moreover, the increase of extracellular CTs in the presence of monoamine uptake blockers point to the presence of functional uptake mechanisms. Altogether, these results indicate the existence of a CT lifecycle in human mononuclear cells and warrant further studies to investigate the role of adrenergic autoregulatory mechanisms in modulation of the immune response and in the pathogenesis of diseases involving the immune system.

Neural and endogenous catecholamines in the bone marrow. Circadian association of norepinephrine with hematopoiesis?

Members of our research team have recently reported that adrenergic agents may affect hematopoies... more Members of our research team have recently reported that adrenergic agents may affect hematopoiesis via alpha1-adrenoceptors present on bone marrow B cell precursors. In this paper we demonstrate that murine bone marrow contains a substantial amount of catecholamines. Norepinephrine (NE) and dopamine (DA) exhibited a daily rhythmicity, with peak values observed during the night. The rhythm was disrupted by chemical sympathectomy, whereas epinephrine (E) showed no rhythmicity or sensitivity to 6-hydroxydopamine. High and low values of NE and DA were associated with high and low values of their metabolites, which indicated a rhythmic catecholamine release. NE, but not DA or E, was positively associated with the proportion of cells in the G2/M and S phases of the cell cycle. Moreover, NE and DA were found in both short-term and long-term bone marrow cultures as well as in human or murine B lymphoid cell lines. These findings indicate that endogenous catecholamines in the bone marrow have both neural and cellular origins. The neural input shows a daily rhythm and may be implicated in the regulation of hematopoiesis.

Catecholamine-producing cells in the synovial tissue during arthritis: modulation of sympathetic neurotransmitters as new therapeutic target

Annals of the rheumatic diseases, 2010

Background The proinfl ammatory and anti-infl ammatory role of the sympathetic nervous system in ... more Background The proinfl ammatory and anti-infl ammatory role of the sympathetic nervous system in early and late infl ammation is an unresolved paradox. A drastic loss of sympathetic nerve fi bres in the synovial tissue of patients with rheumatoid arthritis (RA) has previously been demonstrated. The presence of tyrosine hydroxylase (TH)-positive cells in RA and osteoarthritis (OA) has been determined, but the role of these cells in infl ammation is still unclear.

The first Insubria autumn school on neuroimmunopharmacology: challenging paradigms beyond boundaries

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2013

This issue of the Journal of Neuroimmune Pharmacology is dedicated, in part, to the proceedings o... more This issue of the Journal of Neuroimmune Pharmacology is dedicated, in part, to the proceedings of the First Insubria Autumn School on Neuroimmunopharmacology, organized by Marco Cosentino, Georges J.M. Maestroni, Franca Marino (University of Insubria, Varese, Italy), Manfred Schedlowsky (University of Duisburg-Essen, Germany) and Rainer H. Straub (University of Regensburg, Germany), which took place in November 2011 in Varese, Italy. The School was attended by 50 graduate students and postdoctoral fellows in medical and biological disciplines from 16 european universities and 25 faculties/departments.

Dopaminergic modulation of CD4+CD25(high) regulatory T lymphocytes in multiple sclerosis patients during interferon-β therapy

Neuroimmunomodulation, 2012

paired and DA had no more effect on Treg. In comparison to cells from HCs, Treg from MS patients ... more paired and DA had no more effect on Treg. In comparison to cells from HCs, Treg from MS patients at baseline had increased mRNA for DR D5 and TH (but not for DR D3). During treatment with IFN-␤ , both DR D5 and TH mRNA decreased down to values lower than those of cells from HCs. In comparison to HCs, MS patients had a higher frequency of circulating Treg, both at baseline and after IFN-␤ , while FoxP3 mRNA levels in Treg were similar in patients and HCs and did not show major changes during IFN-␤ . Conclusions: Dopaminergic inhibition of Treg in MS patients is suppressed during IFN-␤ treatment. Treg play a key role in the suppression of autoimmunity, thus the effect may have a therapeutic repercussion.

Expression of apoptosis-related proteins and of mRNA for dopaminergic receptors in peripheral blood mononuclear cells from patients with Alzheimer disease

Alzheimer disease and associated disorders

In search for biomarkers of neurodegeneration, increasing attention has been focussed on peripher... more In search for biomarkers of neurodegeneration, increasing attention has been focussed on peripheral blood mononuclear cells (PBMC). In particular, PBMC from patients with Alzheimer disease (AD) have been suggested to carry apoptotic changes and alterations of neurotransmitter receptor expression, which may resemble those occurring in central nervous system neurons. We investigated the expression of apoptosis-related proteins Bcl-2, Bax, and caspase-3 and the levels of dopaminergic receptors (DR) D3 and D5 mRNA in PBMC from 17 AD patients and 11 age-matched healthy subjects. Apoptosis-related proteins were assayed by standard Western blotting analysis and DR mRNA by real-time polymerase chain reaction techniques. PBMC from healthy subjects and from AD patients expressed Bcl-2, Bax, and caspase-3 to about the same extent, and the Bcl-2/Bax ratio did not differ in the 2 groups. Levels of mRNA for DRD3 and DRD5 were similar in cells from healthy subjects and from AD patients. In conclusion, we found no evidence that PBMC from AD patients may express apoptosis-related proteins or DR mRNA to any different extent in comparison to cells from healthy subjects. These findings do not necessarily imply that immune cells cannot be exploited as biomarkers in AD (and in other central nervous system disorders). Future studies, however, should take into account the inherent complexity of the immune network.

Calcium homeostasis is dysregulated in parkinsonian patients with L-DOPA-induced dyskinesias

Annals of the New York Academy of Sciences, 2003

Long-term treatment of Parkinson disease (PD) is frequently associated with l-3,4-dihydroxyphenyl... more Long-term treatment of Parkinson disease (PD) is frequently associated with l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs). L-DOPA-induced dyskinesias are likely due to changes in the signal transduction pathways, at the striatal level, related to pulsatile stimulation of dopamine receptors. We investigated whether markers of this phenomenon can also be detected peripherally. We analyzed mRNA expression for D5 (D1-like) and D3 (D2-like) receptors and levels of second messengers, such as cAMP and free intracellular Ca2+ ([Ca2+]i), in peripheral blood lymphocytes of PD patients with (LID+) or without LIDs (LID-). Patients with PD showed depressed [Ca2+]i rise in response to mitogen-induced activation. The defect was more pronounced in LID+ (-33% with respect to healthy controls) than in LID- patients (-20%). Peripheral blood lymphocyte levels of cAMP were decreased in both LID+ (3.8 +/- 2.9 pmol/10 cells) and LID- patients (4.2 +/- 2.4 pmol/10(6) cells), with respect to controls (6 +/- 2.6 pmol/10(6) cells). No differences were found in dopamine receptor mRNA expression. Our results demonstrate that second messenger levels are altered in the peripheral blood lymphocytes of PD patients treated with dopaminergic agents and that patients with LIDs show further alterations in the regulation of [Ca2+]i homeostasis. This may represent a distinctive trait of patients prone to develop dyskinetic movements.

Peripheral markers of apoptosis in Parkinson's disease: the effect of dopaminergic drugs

Trends in immunology, 2003

Effects of dopaminergic stimulation on peripheral markers of apoptosis: relevance to Parkinson's disease

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2003

We investigated the effects of dopaminergic stimulation on anti-apoptotic protein Bcl-2, pro-apop... more We investigated the effects of dopaminergic stimulation on anti-apoptotic protein Bcl-2, pro-apoptotic enzyme caspase- 3, and anti-oxidant/anti-apoptotic enzyme Cu/Zn superoxide dismutase (SOD) in human lymphocytes exposed to dopamine (DA). The same determinations were also carried out in parkinsonian patients treated with L-dopa. Caspase-3 activity and Cu/Zn SOD levels tended to increase when lymphocytes were exposed to low or intermediate doses of DA, while a decrease was observed, particularly in caspase-3 activity, with the higher DA dose. Bcl-2 levels were unaffected. In patients, we observed a negative correlation between Cu/Zn SOD levels and daily intake of L-dopa, which also tended to be negatively correlated with caspase-3 activity, but not with Bcl- 2. Our results show that dopaminergic stimulation is associated with complex changes in regulatory proteins of apoptosis.

Unravelling dopamine (and catecholamine) physiopharmacology in lymphocytes: open questions

Trends in immunology, 2003

Evidence for a neuroimmunomodulatory and a hematopoietic role of the Luschka's coccygeal body(3

Neuro endocrinology letters, 2000

OBJECTIVES: In humans the glomus coccygeus was described in 1860 by Luschka. It is present at the... more OBJECTIVES: In humans the glomus coccygeus was described in 1860 by Luschka. It is present at the coccyx tip and corresponds to a complex anastomosis between the median sacral artery and vein, and it is innervated by sympathetic fi bers. In rats and mice it has been located in the tail ventral face. Its function is not known. According to our previous work, which demonstrated that hematopoiesis is under a noradrenergic control and based on the presence of epithelioid cells and sympathetic innervation, we assumed that the coccygeal gland might infl uence hematopoiesis via neuroendocrine or neural mechanisms. Therefore, the present study was undertaken to analyze the effect of glomus coccygeus on hematopoiesis. MATERIAL & METHODS: Peripheral blood leukocyte and platelet concentrations as well as body temperature (BT) and body weight (BW), and norepinephrine (NE), adrenaline (A) and dopamine (DA) content in bone marrow of Luschkaectomized (LCGx), Sham LCGx operated (ShLCGx) and normal mice (Co) were investigated. RESULTS: We found that in LCGx vs. ShLCGx and Co, platelets and neutrophils increased while lymphocytes decreased. The effect of LCGx was signifi cant from day 0 until day 65. Total leukocytes, monocytes, granulocytes, eosinophils and BT did not show any variation. Moreover, 22 days after the operation the amount of NE, A and DA seemed to be decreased in LCGx vs. ShLCGx while the difference was less evident between ShLCGx vs. Co. CONCLUSIONS: This study suggests for the fi rst time a possible hematopoietic function and an immunomodulatory activity of the "Luschka's body" or Coccygeal body by a modulation of the sympathetic nervous system.

FIRST INSUBRIA INTERNATIONAL SCHOOL IN METHODOLOGY, ETHICS AND INTEGRITY IN BIOMEDICAL RESEARCH - Teaching Slides Collection - Volume #5 of 5

School? page 1 SPEAKERS & CHAIRS, ORGANIZING COMMITTEE and SECRETARIAT page 3 SPEAKERS & CHAIRS -... more School? page 1 SPEAKERS & CHAIRS, ORGANIZING COMMITTEE and SECRETARIAT page 3 SPEAKERS & CHAIRS --Biosketches page 5 Module #5 UNDERSTANDING BIOMEDICAL RESEARCH PAPERS page 9 OTHER MODULES Module #1 RESEARCH INTEGRITY Module #2 PRECLINICAL RESEARCH AND LABORATORY ANIMAL CARE AND USE Module #3 HUMAN SUBJECT RESEARCH AND INSTITUTIONAL REVIEW BOARDS Module #4 PUBLISH OR PERISH Per approfondire Che cos'è l'integrità nella ricerca e perché è importante? Esiste una "emergenza etica" nella ricerca scientigica? Researcher bias, publication bias e scienti9ic misconduct 2 Che cos'è l'integrità nella ricerca e perché è importante?

FIRST INSUBRIA INTERNATIONAL SCHOOL IN METHODOLOGY, ETHICS AND INTEGRITY IN BIOMEDICAL RESEARCH - Teaching Slides Collection - Volume #4 of 5

School? page 1 SPEAKERS & CHAIRS, ORGANIZING COMMITTEE and SECRETARIAT page 3 SPEAKERS & CHAIRS -... more School? page 1 SPEAKERS & CHAIRS, ORGANIZING COMMITTEE and SECRETARIAT page 3 SPEAKERS & CHAIRS --Biosketches page 5 Module #4 PUBLISH OR PERISH page 9 OTHER MODULES Module #1 RESEARCH INTEGRITY Module #2 PRECLINICAL RESEARCH AND LABORATORY ANIMAL CARE AND USE Module #3 HUMAN SUBJECT RESEARCH AND INSTITUTIONAL REVIEW BOARDS Module #5 UNDERSTANDING BIOMEDICAL RESEARCH PAPERS Per approfondire Che cos'è l'integrità nella ricerca e perché è importante? Esiste una "emergenza etica" nella ricerca scientigica? Researcher bias, publication bias e scienti9ic misconduct 2 Che cos'è l'integrità nella ricerca e perché è importante?

FIRST INSUBRIA INTERNATIONAL SCHOOL IN METHODOLOGY, ETHICS AND INTEGRITY IN BIOMEDICAL RESEARCH - Teaching Slides Collection - Volume #3 of 5

School? page 1 SPEAKERS & CHAIRS, ORGANIZING COMMITTEE and SECRETARIAT page 3 SPEAKERS & CHAIRS -... more School? page 1 SPEAKERS & CHAIRS, ORGANIZING COMMITTEE and SECRETARIAT page 3 SPEAKERS & CHAIRS --Biosketches page 5 Module #3 HUMAN SUBJECT RESEARCH AND INSTITUTIONAL REVIEW BOARDS page 9 OTHER MODULES Module #1 RESEARCH INTEGRITY Module #2 PRECLINICAL RESEARCH AND LABORATORY ANIMAL CARE AND USE Module #4 PUBLISH OR PERISH Module #5 UNDERSTANDING BIOMEDICAL RESEARCH PAPERS Per approfondire Che cos'è l'integrità nella ricerca e perché è importante? Esiste una "emergenza etica" nella ricerca scientigica? Researcher bias, publication bias e scienti9ic misconduct 2 Che cos'è l'integrità nella ricerca e perché è importante?

FIRST INSUBRIA INTERNATIONAL SCHOOL IN METHODOLOGY, ETHICS AND INTEGRITY IN BIOMEDICAL RESEARCH - Teaching Slides Collection - Volume #2 of 5

School? page 1 SPEAKERS & CHAIRS, ORGANIZING COMMITTEE and SECRETARIAT page 3 SPEAKERS & CHAIRS -... more School? page 1 SPEAKERS & CHAIRS, ORGANIZING COMMITTEE and SECRETARIAT page 3 SPEAKERS & CHAIRS --Biosketches page 5 Module #2 PRECLINICAL RESEARCH AND LABORATORY ANIMAL CARE AND USE page 9 OTHER MODULES Module #1 RESEARCH INTEGRITY Module #3 HUMAN SUBJECT RESEARCH AND INSTITUTIONAL REVIEW BOARDS Module #4 PUBLISH OR PERISH Module #5 UNDERSTANDING BIOMEDICAL RESEARCH PAPERS Per approfondire Che cos'è l'integrità nella ricerca e perché è importante? Esiste una "emergenza etica" nella ricerca scientigica? Researcher bias, publication bias e scienti9ic misconduct 2 Che cos'è l'integrità nella ricerca e perché è importante?

FIRST INSUBRIA INTERNATIONAL SCHOOL IN METHODOLOGY, ETHICS AND INTEGRITY IN BIOMEDICAL RESEARCH - Teaching Slides Collection - Volume #1 of 5

FIRST INSUBRIA INTERNATIONAL SCHOOL IN METHODOLOGY, ETHICS AND INTEGRITY IN BIOMEDICAL RESEARCH -... more

Disregarded Conflicting Results with Prior Research: A Case Report in a Leading Biomedical Journal

by Georges Maestroni and Marco Cosentino

Bibliographic negligence, i.e. omission of citation of the relevant work of other researchers, is... more Bibliographic negligence, i.e. omission of citation of the relevant work of other researchers, is possibly the most common type of research misconduct, leading to unfair loss of priority of authorship and undermining the reward system of science. We report a case of bibliographic negligence which we recently suffered from a leading biomedical journal. The case is discussed in the context of the editorial policy of the journal and of relevant ethical guidelines. Scientific journals should develop codes of conduct for citations. In addition, the implications and consequences of bibliographic negligence deserve thorough investigation.

Transparency for each research article. Institutions must also be accountable for research integrity

BMJ (Clinical research ed.), 2013

The declaration of Helsinki and post-study access to effective drug treatments for subjects participating in clinical trials

Bioethics, 2012

We read with great appreciation the article by Doris Schroeder and Eugenijus Gefenas about benefi... more We read with great appreciation the article by Doris Schroeder and Eugenijus Gefenas about benefit sharing and post-study obligations in medical research. 1 On this topic, while we agree with the analysis and the general conclusions of the authors, we also would like to add some comments on the specific issue of post-study access to therapeutics for subjects participating in clinical trials. Indeed, according to the latest version of the WMA Declaration of Helsinki (paragraph 33):

Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism

Neurology, 2005

The authors report two cases of catechol-O-methyltransferase (COMT) inhibitor-induced asymptomati... more The authors report two cases of catechol-O-methyltransferase (COMT) inhibitor-induced asymptomatic hepatic dysfunction in women with Parkinson disease. The patients were genotyped for the UDP-glucuronosyltransferase (UGT) 1A9 gene (which encodes the main COMT inhibitor-metabolizing enzyme), and found to carry mutations leading to defective glucuronidation activity. This suggests that UGT1A9 poor metabolizer genotype(s) may be a predisposing factor for COMT inhibitor-induced hepatotoxicity. was in charge of the patients and initially observed the cases. Preliminary discussion and planning of the clinical and laboratory assessments were made together with M. Cosentino, M. Ferrari, and F. Marino, in collaboration for the sequencing strategy with G. Porta and E. Mattarucchi. Results were finally examined and discussed for their implications together with S. Lecchini and G. Nappi. M. Cosentino and E. Martignoni wrote the manuscript, and all the authors revised and finally approved the report.

Association between CYP1A2 polymorphisms and clozapine-induced adverse reactions in patients with schizophrenia

Psychiatry research, 2012

We investigated the relationships between common polymorphisms in CYP1A2 (CYP1A2 n 1C and n 1F), ... more We investigated the relationships between common polymorphisms in CYP1A2 (CYP1A2 n 1C and n 1F), CYP1A2-mRNA levels in circulating lymphocytes and clozapine(CLZ)-induced adverse drug reactions (ADRs) in 34 patients. Patients with ADRs had a higher frequency of CYP1A2 low activity allele combinations (8/12; 67%) and lower CYP1A2-mRNA levels than patients without ADRs (6/22; 27%, P ¼ 0.019).

Association of UDP-glucuronosyltransferase 1A9 polymorphisms with adverse reactions to catechol-O-methyltransferase inhibitors in Parkinson's disease patients

European journal of clinical pharmacology, 2012

Purpose To investigate the association between adverse reactions to catechol-O-methyltransferase ... more Purpose To investigate the association between adverse reactions to catechol-O-methyltransferase (COMT) inhibitors and the UDP-glucuronosyltransferase 1A9 genotypes UGT1A9*1b and UGT1A9*3a, which were previously identified in individual cases of COMT inhibitor-induced toxicity. Methods The study included 52 Parkinson’s disease (PD) patients on COMT inhibitors without evidence of adverse reactions and 11 PD patients who had been withdrawn from COMT inhibitors due to adverse reactions. UGT1A9*1b was identified by direct sequencing of the PCR amplification of the gene and UGT1A9*3a was assayed by real-time PCR. Results The frequency of the *3a/*3a and *1/*3a genotype variants was 45.5 % in subjects with adverse reactions and 21.1 % in subjects without adverse reactions [overall UGT1A9*3a allele frequency 27.3 vs. 11.5 %, P = 0.087; odds ratio (OR) 2.87, 95 % confidence interval (CI) 0.94–8.77]. The frequency of genotype combinations leading to low glucuronosyltransferase activity (*3a/*3a irrespective of *1b or *1/*3a and *1/*1b) was 5.8 % in subjects without adverse reactions and 36.4 % in subjects with adverse reactions (P = 0.014; OR 9.33, 95 % CI 1.71–50.78). Conclusions In PD patients UDP-glucuronosyltransferase 1A9 genotypes are associated with adverse reactions to COMT inhibitors, leading to treatment withdrawal. UDP-glucuronosyltransferase 1A9 genotyping may be a screening and/or diagnostic test to assist individualized treatments with COMT inhibitors.

Association between statin-induced creatine kinase elevation and genetic polymorphisms in SLCO1B1, ABCB1 and ABCG2

European journal of clinical pharmacology, 2014

Purpose Treatment with statins requires close monitoring of serum creatine kinase (CK) levels to ... more Purpose Treatment with statins requires close monitoring of serum creatine kinase (CK) levels to prevent myopathy, a common and potentially serious dose-dependent adverse effect of these drugs. We have investigated the correlation between elevated CK levels and polymorphisms in the genes encoding transporters involved in statin disposition. Methods Patients with and without statin-induced elevated serum CK levels were genotyped for polymorphisms in SLCO1B1 (SLCO1B1 A388G and SLCO1B1 T521C), ABCB1 (ABCB1 C1236T and ABCB1 C3435T) and ABCG2 (ABCG2 C421A). Results Patients carrying SLCO1B1 T521C or ABCB1 C1236T single nucleotide polymorphisms (SNPs) had an odds ratio (OR) for statin-induced elevated serum CK levels of 8.86 (p < 0.01) and 4.67 (p < 0.05), respectively, while patients carrying the SLCO1B1 A388G SNP had an OR of 0.24 (p < 0.05). An arbitrary score based on genotype combination discriminated patients with and without CK elevation at a specificity of 97 % and a sensitivity of 39 %. Conclusion Genotyping of the SLCO1B1, ABCB1 and ABCG2 genes deserves consideration as a clinical approach to improve statin safety while concomitantly reducing the burden of blood tests for CK measurements.

Are CYP1A2*1F and *1C associated with clozapine tolerability?: a preliminary investigation

Psychiatry research, 2011

Estrogenic activity of 7-hydroxymatairesinol potassium acetate (HMR/lignan) from Norway spruce (Picea abies) knots and of its active metabolite enterolactone in MCF-7 cells

Pharmacological research : the official journal of the Italian Pharmacological Society, 2007

Lignans are plant polyphenols which may possess anticancer, antioxidant, antimicrobial, anti-infl... more Lignans are plant polyphenols which may possess anticancer, antioxidant, antimicrobial, anti-inflammatory and immunomodulatory activities. In particular, the lignan 7-hydroxymatairesinol (HMR/lignan TM , HMR) is a novel precursor of the mammalian lignan enterolactone (EL). In the present study, we investigated the estrogenicity of HMR and of EL in comparison to estradiol (E2), by measuring their effects on growth and apoptotic markers in the human estrogen-sensitive cell line MCF-7. HMR, EL and E2 concentration-dependently increased the percentage of MCF-7 cells in the S phase of the cell cycle, with the following relative potencies: E2 ∼ = EL HMR, and efficacies: E2 > HMR EL. Treatment of MCF-7 cells with either HMR, EL or E2 also increased the Bcl-2/Bax mRNA ratio. The effects of HMR and EL were reduced in the presence of the estrogen receptor (ER) antagonist tamoxifene. We conclude that both HMR and its metabolite EL are endowed with estrogenic activity, which is likely to be exerted through the contribution of ER-dependent pathways and to target the same intracellular mechanisms acted upon by E2. The estrogenicity of HMR and EL is however milder than that of E2, as indicated by the lower potencies and efficacies of both lignans. The present results support the notion that dietary supplementation with HMR may result in a mild estrogenic activity, both directly and by providing a suitable source for endogenous EL.

Immunomodulatory activity of the lignan 7-hydroxymatairesinol potassium acetate (HMR/lignan) extracted from the heartwood of Norway spruce (Picea abies

International immunopharmacology, 2010

The pharmacological profile of the lignan 7-hydroxymatairesinol (HMR/lignan™, HMR) includes chemo... more The pharmacological profile of the lignan 7-hydroxymatairesinol (HMR/lignan™, HMR) includes chemopreventive effects, antioxidant properties, and mild proestrogenic activity. The present study was devised to investigate the effects of HMR on THP-1 cells, an established model of human monocytes, and on human polymorphonuclear leukocytes (PMNs). In THP-1 cells, HMR concentration-dependently reduced LPSstimulated tumor necrosis factor (TNF)-α secretion in the supernatant. HMR at low, sub-μM concentrations also reduced TNF-α mRNA, which was however enhanced by supra-μM concentrations of HMR. In human PMNs, HMR concentration-dependently reduced ROS production induced by either N-formyl-Met-Leu-Phe, phorbol myristate acetate or angiotensin II, as well as interleukin-8 production induced by either N-formyl-Met-Leu-Phe or angiotensin II. Results indicate that HMR is an effective inhibitor of both monocytic THP-1 cells and of human PMNs and warrant further studies to assess their relevance for the prevention and treatment of several conditions characterized by chronic systemic inflammation.

Effect of the lipopolysaccharide antagonist Planktothrix sp. FP1 cyanobacterial extract on human polymorphonuclear leukocytes

International immunopharmacology, 2011

CyP is a lipopolysaccharide (LPS)-like molecule extracted from the freshwater cyanobacterium Osci... more CyP is a lipopolysaccharide (LPS)-like molecule extracted from the freshwater cyanobacterium Oscillatoria planktothrix FP1, which has been reported to be a potent competitive inhibitor of bacterial LPS. In the present study the ability of CyP to affect human polymorphonuclear leukocyte (PMN) function was investigated. PMNs were isolated from venous blood by standard density-gradient centrifugation. Cell migration was measured by use of the Boyden chamber assay. Interleukin (IL)-8 and tumor necrosis factor (TNF)-α production was measured using a sandwich-type enzyme-linked immunosorbent assay. PMN intracellular reactive oxygen species (ROS) levels were assessed by the use of a fluorescent probe coupled to spectrophotometry. CyP 10-100 μg/ml was chemotactic for PMNs without affecting the chemotactic response to either E. coli LPS or N-formyl-Met-Leu-Phe (fMLP). CyP per se did not affect PMN production of either IL-8 or TNF-α, but concentration-dependently reduced LPS-induced production of both cytokines. On the contrary, CyP had no effect either on fMLP-induced production of IL-8 or on PMN oxidative burst (at rest and after stimulation with fMLP), a response which is known to be independent from LPS-operated pathways. In human PMNs CyP behaves as a selective and effective LPS antagonist. These findings support the therapeutic potential of CyP in endotoxin-dependent disease.

Immunomodulatory properties of Achyrocline satureioides (Lam.) D.C. infusion: a study on human leukocytes

Journal of ethnopharmacology, 2008

Aim of the study: Achyrocline satureioides (Lam.) D.C. is a South American native medicinal herb ... more Aim of the study: Achyrocline satureioides (Lam.) D.C. is a South American native medicinal herb known by the popular name of "Marcela". Its infusion is widely utilized for the treatment of several digestive ailments, as an anti-inflammatory preparation, as a sedative and anti-atherosclerotic. Circumstantial evidence suggests that extracts of Achyrocline satureioides may have immunomodulatory properties. The present study was therefore devised to investigate the in vitro effects Achyrocline satureioides infusion on human peripheral blood mononuclear cells (PBMCs) and polymorphonuclear leukocytes (PMNs). Materials and methods: Experiments were performed on cells isolated from venous blood obtained from healthy donors. PBMC proliferation and cytokine production were assessed by standard ELISA methods. Reactive oxygen species (ROS) production by PMNs was evaluated by spectrofluorimetry. Results: In PBMCs, Achyrocline satureioides infusion in the 0.06-0.24 g/ml quercetin equivalent (QE) concentration range concentrationdependently reduced PHA-induced proliferation and production of interferon (IFN)-␥ and interleukin (IL)-4. Lower concentrations of the infusion (0.006-0.03 g/ml QE), which were ineffective on cell proliferation, significantly increased the production of both IFN-␥ and IL-4 and decreased the ratio IFN-␥/IL-4. In PMNs, Achyrocline satureioides infusion slightly increased the spontaneous generation of ROS only at concentrations ≥0.06 g/ml QE. On the contrary, in the 0.0012-0.03 g/ml QE concentration range the infusion profoundly inhibited fMLP-induced ROS generation as well as spontaneous and fMLP-induced IL-8 production.

Antioxidant and cytoprotective properties of infusions from leaves and inflorescences of Achillea collina Becker ex Rchb

Phytotherapy research : PTR, 2009

Plants are the main source of molecules with antioxidant and radical scavenging properties that a... more Plants are the main source of molecules with antioxidant and radical scavenging properties that aid the natural defence systems of cells and may be involved in the preservation of human health, particularly preventing all the physiopathological conditions where oxidative damage is a hallmark. Achillea collina Becker ex Rchb. is a medicinal plant of the Achillea millefolium aggregate (yarrow) traditionally used, particularly in mountain areas, as an infusion or alcohol extract for its digestive, antiinflammatory, analgesic, antipyretic and wound healing properties. The aim of this study was to investigate the antioxidant capacity and cytoprotective activity against oxidative stress of infusions obtained from the leaves and inflorescences of Achillea collina Becker ex Rchb., assessed by chemical (free radical scavenging activity by DPPH and Folin Ciocalteu assay) and biological assays (in vitro model of cytotoxicity and lipid peroxidation in PC12 cells line). Infusions of leaves had the highest antioxidant properties and cytoprotective activity. The antioxidant capacity was significantly correlated with the total phenolic content but not with the cytoprotective profile. Achillea collina Becker ex Rchb. has good antioxidant and cytoprotective properties, suggesting further investigations on its chemical composition and potential health value, particularly for traditionally prepared infusions of leaves. Copyright © 2008 John Wiley & Sons, Ltd.

Effect of the lipopolysaccharide antagonist Planktothrix sp. FP1 cyanobacterial extract on human polymorphonuclear leukocytes

by Franca Marino, Carlo Rossetti, and Marco Cosentino

International Immunopharmacology, 2011

CyP is a lipopolysaccharide (LPS)-like molecule extracted from the freshwater cyanobacterium Osci... more CyP is a lipopolysaccharide (LPS)-like molecule extracted from the freshwater cyanobacterium Oscillatoria planktothrix FP1, which has been reported to be a potent competitive inhibitor of bacterial LPS. In the present study the ability of CyP to affect human polymorphonuclear leukocyte (PMN) function was investigated. PMNs were isolated from venous blood by standard density-gradient centrifugation. Cell migration was measured by use of the Boyden chamber assay. Interleukin (IL)-8 and tumor necrosis factor (TNF)-α production was measured using a sandwich-type enzyme-linked immunosorbent assay. PMN intracellular reactive oxygen species (ROS) levels were assessed by the use of a fluorescent probe coupled to spectrophotometry. CyP 10-100 μg/ml was chemotactic for PMNs without affecting the chemotactic response to either E. coli LPS or N-formyl-Met-Leu-Phe (fMLP). CyP per se did not affect PMN production of either IL-8 or TNF-α, but concentration-dependently reduced LPS-induced production of both cytokines. On the contrary, CyP had no effect either on fMLP-induced production of IL-8 or on PMN oxidative burst (at rest and after stimulation with fMLP), a response which is known to be independent from LPS-operated pathways. In human PMNs CyP behaves as a selective and effective LPS antagonist. These findings support the therapeutic potential of CyP in endotoxin-dependent disease.

Effects of a commercial product containing guaraná on psychological well-being, anxiety and mood: a single-blind, placebo-controlled study in healthy subjects

Journal of negative results in biomedicine, 2013

Background: Guaranà (Paulinia cupana) seed extracts are increasingly popular worldwide for their ... more Background: Guaranà (Paulinia cupana) seed extracts are increasingly popular worldwide for their stimulant, cognitive and behavioral effects. To assess the effects on psychological well-being, anxiety and mood of a commercially available guaranà preparation taken regularly over several days according to the labelled dosages and instructions, 27 healthy volunteers were enrolled in a prospective, randomized, single-blind, placebo-controlled, crossover study. Results: Guaranà 350 mg × 3 daily just after breakfast or placebo were given for 5 consecutive days. Assessment was performed one day after the last intake and included the psychological well-being (PWB) scales, the self-rating anxiety state scale (SAS), and the Bond-Lader mood scales. There were no significant differences between guaranà and placebo in any of the 6 areas of PWB, in SAS, as well as in any of the 16 mood scales.

Isoflavone content and estrogenic activity of different batches of red clover (Trifolium pratense L.) extracts: An in vitro study in MCF-7 cells

Fitoterapia, 2014

The estrogenicity of different batches of red clover (Trifolium pratense L., Fabaceae; RCL) extra... more The estrogenicity of different batches of red clover (Trifolium pratense L., Fabaceae; RCL) extracts and its relationship with the isoflavone content were assessed by measuring MCF-7 cell proliferation by flow cytometry and propidium iodide staining. RCL extracts were compared to estradiol (E2) and to the main RCL isoflavones biochanin A, daidzein, genistein and formononetin. Isoflavone content in the extracts was assayed by HPLC. E2 and isoflavones increased MCF-7 proliferation in a concentration-dependent fashion, with the following potency order: E2 NNN genistein N biochanin A = daidzein N formononetin. Extracts increased MCF-7 proliferation with different potencies, which in four out of five extracts correlated with the ratios 5,7-dihydroxyisoflavones/7-hydroxyisoflavones. The efficacy of all extracts increased with decreasing genistein contents. A solution containing the main isoflavones at the average concentration of RCL extracts increased MCF-7 proliferation with higher potency and steeper concentration-response curve. The effects of E2, of RCL extracts and of the isoflavone solution were inhibited by the estrogen receptor antagonist 4-hydroxytamoxifen. Flow cytometric analysis of MCF-7 proliferation is a suitable bioassay for the estrogenicity of RCL extracts, thus expanding the characterization of individual batches beyond assessment of chemical composition and contributing to improved standardization of quality and activity.

The Essential Oil of Bergamot Stimulates Reactive Oxygen Species Production in Human Polymorphonuclear Leukocytes

Phytotherapy research : PTR, 2014

Bergamot (Citrus aurantium L. subsp. bergamia) essential oil (BEO) is used in folk medicine as an... more Bergamot (Citrus aurantium L. subsp. bergamia) essential oil (BEO) is used in folk medicine as an antiseptic and anthelminthic and to facilitate wound healing. Evidence indicates that BEO has substantial antimicrobial activity; however its effects on immunity have never been examined. We studied the effects of BEO on reactive oxygen species (ROS) production in human polymorphonuclear leukocytes (PMN) and the role of Ca2+ in the functional responses evoked by BEO in these cells. Results show that BEO increased intracellular ROS production in human PMN, an effect that required the contribution of extracellular (and, to a lesser extent, of intracellular) Ca2+. Bergamot essential oil also significantly increased ROS production induced by the chemotactic peptide N-formyl-Met-Leu-Phe and reduced the response to the protein kinase C activator phorbol myristate acetate. In conclusion, this is the first report showing the ability of BEO to increase ROS production in human PMN. This effect could both contribute to the activity of BEO in infections and in tissue healing as well as underlie an intrinsic proinflammatory potential. The relevance of these findings for the clinical uses of BEO needs careful consideration. Copyright © 2014 John Wiley & Sons, Ltd.

Medical healthcare use in Parkinson's disease: survey in a cohort of ambulatory patients in Italy

BMC health services research, 2005

Background: Parkinson's disease (PD) is a chronic neurodegenerative disease which at present has ... more Background: Parkinson's disease (PD) is a chronic neurodegenerative disease which at present has no cure, and it usually results in severe disability. The burden of PD increases as the illness progresses, resulting in the extensive utilisation of both health and community services. Knowledge of healthcare use patterns and of their determinants may greatly contribute to improve patient care, however few studies have examined this issue in PD. The present study was devised to describe the type of and reasons for medical healthcare resource use in persons with PD attending a Centre for PD and Movement Disorders, and to examine drug prescriptions issued on such occasions.

Drug prescribing patterns in Parkinson's disease: a pharmacoepidemiological survey in a cohort of ambulatory patients

Pharmacoepidemiology and drug safety, 2002

PurposeDrug treatment of idiopathic Parkinson's disease (IPD) is a difficult task, and comorbidit... more PurposeDrug treatment of idiopathic Parkinson's disease (IPD) is a difficult task, and comorbidity and comedication add to its complexity. Since in IPD there is little information about drug use, this study investigated drug prescribing and indications in IPD patients.Drug treatment of idiopathic Parkinson's disease (IPD) is a difficult task, and comorbidity and comedication add to its complexity. Since in IPD there is little information about drug use, this study investigated drug prescribing and indications in IPD patients.MethodsFrom June 1997 to April 1998, a cross-sectional survey of IPD outpatients was performed and demographic and clinical data and information about drug treatments was collected and analysed.From June 1997 to April 1998, a cross-sectional survey of IPD outpatients was performed and demographic and clinical data and information about drug treatments was collected and analysed.ResultsIn the 130 IPD patients included in the study, anti-Parkinson drug (APD) prescriptions increased with disease duration and severity. Levodopa was most frequently used, followed by dopamine agonists and anticholinergic agents. Levodopa with other APDs was given to older patients with later IPD onset. Prescriptions of drugs for other indications (non-APDs) were given to 80.8% of the patients and their number increased with patient age. Non-APD prescriptions concerned mainly the circulatory system, mental disorders, the musculo-skeletal system and the digestive system. Prescriptions for indications corresponding to secondary symptoms that often complicate IPD increased with patient age and also with IPD duration.In the 130 IPD patients included in the study, anti-Parkinson drug (APD) prescriptions increased with disease duration and severity. Levodopa was most frequently used, followed by dopamine agonists and anticholinergic agents. Levodopa with other APDs was given to older patients with later IPD onset. Prescriptions of drugs for other indications (non-APDs) were given to 80.8% of the patients and their number increased with patient age. Non-APD prescriptions concerned mainly the circulatory system, mental disorders, the musculo-skeletal system and the digestive system. Prescriptions for indications corresponding to secondary symptoms that often complicate IPD increased with patient age and also with IPD duration.ConclusionIn IPD patients, disease duration and severity and patient age seem to be major determinants of drug use. Indications for drug prescription suggest that main comorbidity includes neuropsychiatric, circulatory, musculo-skeletal and digestive disorders. Analysis of prescribing patterns in IPD can provide a readily accessible indirect indicator of patient health status for both health services and epidemiologic research purposes. Copyright © 2002 John Wiley & Sons, Ltd.In IPD patients, disease duration and severity and patient age seem to be major determinants of drug use. Indications for drug prescription suggest that main comorbidity includes neuropsychiatric, circulatory, musculo-skeletal and digestive disorders. Analysis of prescribing patterns in IPD can provide a readily accessible indirect indicator of patient health status for both health services and epidemiologic research purposes. Copyright © 2002 John Wiley & Sons, Ltd.

Hospital‐based survey of doctors' attitudes to adverse drug reactions and perception of drug‐related risk for adverse reaction occurrence

Pharmacoepidemiology and Drug Safety, 1999

Doctors' attitudes to adverse drug reactions (ADRs) and perception of drug-related risk for ADR o... more Doctors' attitudes to adverse drug reactions (ADRs) and perception of drug-related risk for ADR occurrence were investigated in four hospitals in Northern Italy using an interviewer-administered questionnaire. ADRs were a relevant concern in medical practice for 80% of the respondents and had been observed by 87%. ADRs were perceived to occur in no more than 5% of hospitalized patients and serious ADRs in less than 1%. The response patterns, however, diered according to the ward of work and the year of graduation of the doctors. Antibacterials, NSAIDs and antiarrhythmics were rated as higher risk drugs, while diuretics, lipid lowering agents, antihistamines, antiemetics and antispasmodics were rated as lower risk drugs. Risk perception was dishomogeneous mainly with respect to the ward of work. The estimated frequency of ADR occurrence, the perception of drug-related risk and previous ADR reporting behaviour were clearly correlated. The present results suggest that personal factors aect doctors' attitudes to ADRs, perception of drug-related risk and ADR reporting behaviour and may thus be relevant in developing and targeting educational strategies aimed at increasing awareness of ADRs and at encouraging ADR reporting.

ATTITUDES TO ADVERSE DRUG REACTION REPORTING BY MEDICAL PRACTITIONERS IN A NORTHERN ITALIAN DISTRICT

Pharmacological Research, 1997

Attitudes to adverse drug reaction (ADR) spontaneous reporting were investigated among all the Na... more Attitudes to adverse drug reaction (ADR) spontaneous reporting were investigated among all the National Health Service (NHS) doctors operating in the territory of the Area Health Authority n.1 of Varese (Italy), to assess their awareness of the reporting system and to identify reasons for under reporting. Three hundred and fifty doctors were sent questionnaires and 207 (59.1%) were returned completed. More than 77% of the responders stated to have noticed ADRs, which were mainly reported to the pharmaceutical manufacturers and, in a minority of cases, to the NHS. Fifty per cent did not report ADRs to anyone. Important factors for deciding to report were unusualness and severity of the reaction, and involvement of a new drug. The main reason for not reporting was the clinical negligibility of the reaction. There was little knowledge about the types of reactions to be preferentially reported and the purposes of ADR reporting systems. Nevertheless, nearly everyone asked for feed-back information about reported ADRs. NHS doctors in this district have little information concerning ADR reporting systems. Some effective measures to improve the situation could be: inclusion of pharmacovigilance into pre-and post-graduated continuing education programs, provision of guidelines for ADR spontaneous reporting and of feed-back information to reporters, implementation of regional pharmacovigilance units.

An approach for the estimation of drug prescribing using the defined daily dose methodology and drug dispensation data

European Journal of Clinical Pharmacology, 2000

Objective: To test the hypothesis that comparison of defined daily dose (DDD) and drug user data ... more Objective: To test the hypothesis that comparison of defined daily dose (DDD) and drug user data may help to estimate drug exposure in a defined population and provide information about drug prescribing patterns. Methods and results: First, comparison of DDD figures with the number of apparent drug users (ADU, i.e., individuals for whom at least one prescription of the drug had been dispensed during a given time period) is demonstrated to correspond to the product of the prescribed daily dose (PDD) and the proportion of days in which the drug had been taken (days of treatment/days in a time period, D). The resulting equation (DDD/day)/ADU in a time period=PDD × D is then applied to the analysis of different sets of drug dispensation data. Examples show that this approach may be helpful to monitor drug prescribing patterns over time. Moreover, in definite situations, it may provide reliable estimates of either PDD or D. Conclusions: Comparison of DDD and drug user data is suggested to be a cost-effective strategy to monitor drug prescribing patterns from an epidemiological perspective, which may be useful to researchers involved in drug utilisation studies as well as to health authorities for monitoring and regulatory purposes.

An approach for the estimation of drug prescribing using the defined daily dose methodology and drug dispensation data. Theoretical considerations and practical applications

European journal of clinical pharmacology, 2000

Objective: To test the hypothesis that comparison of de®ned daily dose (DDD) and drug user data m... more Objective: To test the hypothesis that comparison of de®ned daily dose (DDD) and drug user data may help to estimate drug exposure in a de®ned population and provide information about drug prescribing patterns. Methods and results: First, comparison of DDD ®gures with the number of apparent drug users (ADU, i.e., individuals for whom at least one prescription of the drug had been dispensed during a given time period) is demonstrated to correspond to the product of the prescribed daily dose (PDD) and the proportion of days in which the drug had been taken (days of treatment/days in a time period, D). The resulting equation (DDD/day)/ ADU in a time period PDD´D is then applied to the analysis of dierent sets of drug dispensation data. Examples show that this approach may be helpful to monitor drug prescribing patterns over time. Moreover, in de®nite situations, it may provide reliable estimates of either PDD or D. Conclusions: Comparison of DDD and drug user data is suggested to be a cost-eective strategy to monitor drug prescribing patterns from an epidemiological perspective, which may be useful to researchers involved in drug utilisation studies as well as to health authorities for monitoring and regulatory purposes.

A 1-year study of drug prescriptions and adverse drug reactions in psychiatric hospital practice

Pharmacoepidemiology and drug safety, 1996

Drug prescribing habits and adverse drug reaction occurrence were investigated in a psychiatric h... more Drug prescribing habits and adverse drug reaction occurrence were investigated in a psychiatric hospital ward for chronic resident patients, and the usefulness of a drug prescription and adverse event (AE) routine monitoring programme in this setting was assessed. A computerized data base was established and updated bimonthly with clinical data concerning each patient. In particular, information about drug prescriptions was routinely obtained from the clinical records, stored in the data base and periodically retrieved and analysed. The ward doctors were required to report on a form the AEs, which were subsequently examined by a panel of clinical pharmacologists and hospital consultants, to assess their relationship with drug treatments. Moreover, the data base was periodically scrutinized, to search for further AEs. Drug prescription monitoring, besides providing valuable information about drug utilization, allowed identification of some questionable issues (e.g. polypharmacy, low frequency of treatment revisions). The AE monitoring system proved to be effective and the participation of the ward doctors was satisfactory. It is concluded that in this psychiatric hospital setting a drug prescription and AE routine monitoring programme can provide useful information and promote improvement of the quality of care.

An unusual systemic reaction associated with topical salicylic acid in a paediatric patient

British journal of clinical pharmacology, 2008

Hepatotoxicity after high-dose methylprednisolone for demyelinating disease

Clinical neuropharmacology

Liver toxicity, although not mentioned among the possible adverse effects of corticosteroids, has... more Liver toxicity, although not mentioned among the possible adverse effects of corticosteroids, has been occasionally reported in literature. We observed 2 cases of hepatotoxicity after a high-dose methylprednisolone treatment of a demyelinating disease and evaluated the potential relationship in the light of available evidence. The first patient developed a histologically documented acute hepatitis and recovered after 3 weeks. In the second patient, a mild augmentation of liver enzymes occurred, followed by normalization in a few days. The causal relationship between hepatotoxicity and methylprednisolone treatment was deemed probable in both cases. Careful review of the literature suggests that corticosteroid-induced liver damage may be more frequent than commonly believed.

Increased reporting of adverse reactions to ACE inhibitors associated with limitations to drug reimbursement for angiotensin-II receptor antagonists

European journal of clinical pharmacology, 2001

, the Italian Ministry of Health limited angiotensin-II type-1 (AT 1 ) receptor antagonist reimbu... more , the Italian Ministry of Health limited angiotensin-II type-1 (AT 1 ) receptor antagonist reimbursement only to patients who necessitated discontinuation of angiotensin converting enzyme (ACE) inhibitor treatment due to cough or angioedema. We assessed the consequences of this decision on the reporting of ACE inhibitor-associated adverse drug reactions (ADRs). Methods: ACE inhibitor-associated ADRs reported to the national pharmacovigilance system in 1997±2000 in the district of Varese (northern Italy, more than 820,000 inhabitants) were retrieved and analysed. The dispensation of ACE inhibitors and AT 1 receptor antagonists reimbursed by the National Health System was also examined. Results: There were 228 reports of ACE inhibitor-associated ADRs, and cough was the ADR reported in 93.4% of cases. There were no reports

Selling androgenic anabolic steroids by the pound: identification and analysis of popular websites on the Internet

Scandinavian journal of medicine & science in sports, 2011

Internet websites offering androgenic anabolic steroids (AAS) were identified and available produ... more Internet websites offering androgenic anabolic steroids (AAS) were identified and available products were examined. Keywords for the website search were: “anabolic steroids,” “anabolic steroids buy,” “anabolic steroid purchase.” The first 10 websites offering AAS in the first 10 pages of results were considered. At least two AAS-containing products per website were selected. Thirty AAS-selling websites were identified, mainly located in the United States (46.7%) and Europe (30%). Most websites sold other anabolic/ergogenic products (clenbuterol, 76.7%; GH/IGF, 60.0%; thyroid hormones, 46.7%; erythropoietin, 30.0%; insulin, 20.0%) or products for AAS-related adverse effects (mainly: estrogen antagonists, 63.3%; products for erectile dysfunction, 56.7%; 5α-reductase inhibitors, 33.3%; anti-acne products, 33.3%). AAS were sold as medicines (69.6%) or as dietary supplements (30.4%). AAS in medicines were mainly: nandronole (20.4%), methandrostenolone (18.4%), and testosterone (12.2%). Dietary supplements contained mainly DHEA and included several fake compounds. Manufacturers were declared for 97.9% of medicines and 66.7% of dietary supplements; however, several manufacturers were not found on the Internet. Described benefits were usually few adverse effects and no estrogenicity. Toxicity was seldom reported and presented as mild. Recommended doses were two–fourfold higher than current medical recommendations. In conclusion, misleading information and deceiving practices were common findings on AAS-selling websites, indicating their deleterious potential for public health.

Dietary Supplement and Drug Use and Doping Knowledge and Attitudes in Italian Young Elite Cyclists

Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine, 2013

Objective: To explore use and attitudes toward drugs and dietary supplements (DS) and knowledge c... more Objective: To explore use and attitudes toward drugs and dietary supplements (DS) and knowledge concerning doping in cycling. Design: Retrospective cross-sectional study. Setting: Professional cycling. Participants: Elite under-23 male cyclists. Intervention: Anonymous semistructured questionnaire administered during race periods. Main Outcome Measures: Use and attitudes toward DS and drugs, and doping knowledge.

Simvastatin down-regulates the production of Interleukin-8 by neutrophil leukocytes from dyslipidemic patients

BMC cardiovascular disorders, 2014

Background: Neutrophil (PMN) leukocytes participate to the initial phases of atherosclerosis thro... more Background: Neutrophil (PMN) leukocytes participate to the initial phases of atherosclerosis through the release of Interleukin 8 (CxCL8; IL-8) that contribute to amplification of inflammation. Aim of the study is to investigate the production of IL-8 by PMN leukocytes from dyslipidemic patients treated with simvastatin. Methods: In 15 dyslipidemic subjects with moderately increased cardiovascular risk, assessed by Framingham Risk Score, blood samples were obtain to investigate PMNs IL-8 production [at baseline and after N-formyl-Met-Leu-Phe (fMLP) stimulation] before and after long-term (1-year) simvastatin treatment. Results: The resting release of IL-8 was higher in dyslipidemic patients at baseline when compared with control subjects (p < 0.05). One year of treatment was significantly associated with reduced IL-8 production (p < 0.01). Moreover, the fMLP-induced IL-8 production in dyslipidemic untreated patients was higher than that of controls (p < 0.05) and was reduced after simvastatin treatment (p < 0.01). IL-8 release after 1 year of treatment was reduced to levels which were lower than those observed in control subjects both for resting and stimulated cytokine production (p < 0.01). Conclusions: Prolonged treatment with simvastatin is associated with a reduction of IL-8 production, suggesting the possibility of statin to modulate the pro-inflammatory response in PMNs of patients with moderately increased cardiovascular risk.

Foxp3 Expressing CD4 + CD25 + and CD8 +CD28 − T Regulatory Cells in the Peripheral Blood of Patients with Lung Cancer and Pleural Mesothelioma

Human Immunology, 2006

The role of T regulatory (Treg) cells in human cancer has not yet been clarified. We assessed the... more The role of T regulatory (Treg) cells in human cancer has not yet been clarified. We assessed the presence and function of CD4 ϩ and CD8 ϩ Treg cell subsets in the peripheral blood of patients with lung cancer (LC) and pleural mesothelioma (PM). We found a low but significant increase in the number of CD4 ϩ T cells with phenotype and functional features of Treg cells in LC patients compared to normal healthy controls (NHC). Furthermore, total CD4 ϩ T cells from LC patients proliferated less than cells from controls, suggesting that the increase in the CD4 ϩ Treg cell pool has functional importance. LC patients also showed an expansion of the CD8 ϩ CD28 Ϫ T cell subset and these cells expressed Foxp3 mRNA, as recently observed in alloantigen-specific CD8 ϩ CD28 Ϫ T suppressor cells. No varia-tion of peripheral Treg cell subsets was found in patients with PM, a disease with a predominantly localized nature. However, the lack of correlation between cancer stage and the number or the function of peripheral Treg cells in LC patients refuted the hypothesis that these cells are involved in tumor spreading. A possible involvement of the peripheral Treg cell pool in cancer development and/or in inducing systemic immunosuppression in LC patients can be hypothesized.

Assessment of lymphocyte subsets and neutrophil leukocyte function in chronic psychiatric patients on long-term drug therapy

Progress in neuro-psychopharmacology & biological psychiatry, 1996

Immunological adverse effects of anticonvulsants. What is their clinical relevance

Drug safety : an international journal of medical toxicology and drug experience, 1993

Long term administration of anticonvulsants is sometimes associated with impairment of the humora... more Long term administration of anticonvulsants is sometimes associated with impairment of the humoral and/or cellular immune response. Furthermore, certain well known adverse reactions to antiepileptics may have an immunotoxicological origin e.g. lymphadenopathy, pseudolymphoma and systemic lupus erythematosus. However, two important questions remain unresolved. First, the possibility that epilepsy per se might be primarily associated with immune alterations makes it difficult to assess the pathogenetic role of a specific drug, especially in a patient population usually on multiple drug therapy. Secondly, the clinical relevance of some of the observed immunological abnormalities is still highly controversial. This review is intended to give an outline of the present state of knowledge on the effects of anticonvulsants on humoral, cellular and nonspecific immunity, with particular regard to some of the major clinical conditions that have been ascribed to drug-induced immune dysregulation, such as pseudolymphoma and systemic autoimmune diseases. The immunotoxic potential of anticonvulsants appears to be low, and immunological monitoring is not usually required except in patients with known immune defects.

Carbamazepine affects neutrophil function through an action on peripheral benzodiazepine receptors

Immunopharmacology and immunotoxicology, 1997

The aims of this study were to assess the possible role of peripheral benzodiazepine receptors (p... more The aims of this study were to assess the possible role of peripheral benzodiazepine receptors (pBZrs)1 in mediating the in vitro effects of carbamazepine (CBZ) on some neutrophil functions in healthy volunteers and to investigate neutrophil function and pBZr expression in patients with epilepsia on CBZ monotherapy for at least 1 year. In vitro CBZ (42-168 microM) concentration-dependently inhibited chemotaxis induced by N-formyl-methionyl-leucyl-phenylalanine (FMLP) or lipopolysaccharide (LPS)-activated human serum. CBZ did not affect random migration, phagocytosis index, phagocytosis frequency, NBT reduction frequency, C. albicans lethality index and resting superoxide production. The pBZr antagonist PK 11195 (1 microM, per se ineffective) reversed the inhibitory effect of CBZ on chemotaxis induced by endotoxin-activated serum or FMLP. The pBZr agonist Ro 5-4864 (10-100 microM) mimicked the effect of CBZ on chemotaxis induced by endotoxin-activated serum or FMLP and had no effect on the other parameters. Neutrophils from epileptic patients on chronic CBZ monotherapy had impaired FMLP- and serum-induced chemotaxis and enhanced expression of pBZrs on neutrophils. These data strongly suggest an involvement of pBZrs in mediating the in vitro effects of CBZ on chemotaxis; furthermore, impairment of the same neutrophil function parameters and overexpression of pBZrs in patients are consistent with the hypothesis of an in vivo interaction of CBZ with pBZrs.

Thyroid hormone regulation of cell migration and oxidative metabolism in polymorphonuclear leukocytes: clinical evidence in thyroidectomized subjects on thyroxine replacement therapy

Life sciences, 2006

À ) generation were studied in polymorphonuclear leukocytes (PMNs) from 14 athyreotic patients, p... more À ) generation were studied in polymorphonuclear leukocytes (PMNs) from 14 athyreotic patients, previously treated by total thyroidectomy and radioiodine therapy for differentiated thyroid carcinoma, and from age-and sex-matched euthyroid healthy controls. Patients were studied twice: in hypothyroidism (visit 1) and after TSH-suppressive L-T 4 replacement therapy (visit 2). Random migration and N-formyl-Met-Leu-Phe (fMLP) 0.1-AM induced chemotaxis were similar in cells from patients at both visit 1 and visit 2 and from healthy controls. On the contrary, resting O 2 À generation in cells from patients was significantly lower than control values, both at visit 1 and 2. At visit 1, fMLP 0.1 AM-induced O 2 À generation was significantly lower than control values, while phorbol-myristate acetate (PMA) 100-ng/ml induced O 2 À generation was similar in cells from patients and from controls. At visit 2 both responses increased, resulting in fMLP-induced O 2 À generation superimposable to control values and PMA-induced O 2 À generation significantly higher with respect to both visit 1 and cells from controls. In vitro exposure of PMNs from healthy subjects to L-T 4 did not affect O 2 À generation in resting cells, and significantly increased that induced by fMLP or PMA only at high, supra-physiological concentrations. Neither TSH nor T 3 had significant effects at any of the concentrations tested. The present results document the existence of a correlation between thyroid status and oxidative metabolism of human PMNs, which is however unlikely to depend upon a direct action of thyroid hormones on these cells.

Prolonged statin-associated reduction in neutrophil reactive oxygen species and angiotensin II type 1 receptor expression: 1-year follow-up

European heart journal, 2008

Our study investigated reactive oxygen species (ROS) generation and angiotensin II type 1 recepto... more

Modulation of intracellular calcium in human neutrophils by peripheral benzodiazepine receptor ligands

Journal of chemotherapy (Florence, Italy), 1998

Diazepam stimulates migration and phagocytosis of human neutrophils: possible contribution of peripheral-type benzodiazepine receptors and intracellular calcium

Pharmacology, 2001

In isolated human neutrophils, diazepam (10 nmol/l to 10 micromol/l) concentration-dependently in... more In isolated human neutrophils, diazepam (10 nmol/l to 10 micromol/l) concentration-dependently increased migration and phagocytosis. Diazepam-induced migration and phagocytosis were inhibited by the peripheral benzodiazepine receptor (PBR) antagonist PK11195 (10 micromol/l). The PBR agonist Ro5-4864 (10 nmol/l to 10 micromol/l) did not affect migration but slightly enhanced phagocytosis, while clonazepam, which binds to the central-type benzodiazepine receptors but has no affinity for PBRs, was ineffective on both parameters up to 10 micromol/l. Phagocytosis induced by diazepam or Ro5-4864 was inhibited by the Ca2+ channel blocker L-verapamil (10 micromol/l), which however did not affect the action of diazepam on migration. Competition binding experiments performed by fluorescent staining of PBRs showed that diazepam directly interacts with PBRs on human neutrophils. Both diazepam and Ro5-4864 (10 nmol/l to 10 micromol/l) induced a rise of intracellular free Ca2+ concentrations ([Ca2+]i), which was inhibited by PK11195 (10 micromol/l) and L-verapamil (10 micromol/l) and prevented by extracellular Ca2+ chelation with EGTA (5 mmol/l). In conclusion, experimental evidence indicates that in human neutrophils diazepam stimulates both migration and phagocytosis through activation of PBRs. Diazepam-induced [Ca2+]i changes depend on a PBR-operated, L-verapamil-sensitive increase in the plasma membrane permeability and subsequent extracellular Ca2+ entry, and contribute to diazepam-induced phagocytosis. On the contrary, the effect of diazepam on migration seems to occur through Ca2+ -independent mechanisms.

Thyroid hormone and thyrotropin regulate intracellular free calcium concentrations in human polymorphonuclear leukocytes: in vivo and in vitro studies

International journal of immunopathology and pharmacology

Intracellular free calcium concentrations (Ca++i) were studied in polymorphonuclear leukocytes (P... more Intracellular free calcium concentrations (Ca++i) were studied in polymorphonuclear leukocytes (PMNs) from 13 athyreotic patients who had been previously treated by total thyroidectomy and radioiodine therapy for differentiated thyroid carcinoma, and from age- and sex-matched euthyroid healthy controls. Patients were studied twice, when hypothyroid (visit 1) and after restoration of euthyroidism by L-T4 TSH-suppressive therapy (visit 2). PMNs from patients at visit 1 had significantly lower resting (Ca++)i levels compared to both visit 2 and controls. Values at visit 2 did not differ from those of the controls. Stimulus-induced (Ca++)i rise was also significantly blunted at visit 1 and normalized at visit 2, possibly through a differential contribution of distinct intracellular Ca++ stores, as suggested by the response pattern to the chemotactic agent, N-formyl-Met-Leu-Phe (fMLP), to the selective SERCA pump inhibitor, thapsigargine, and to the mitochondrial uncoupler, carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP). In vitro treatment of PMNs from healthy subjects with high TSH concentrations impaired intracellular Ca++ store function. Both resting (Ca++)i levels and fMLP-induced (Ca++)i rise increased in the presence either of low-concentration TSH or of T4, but effects of TSH and T4 were not additive. T3, rT3, and TRIAC had no effect. In conclusion, this study provides evidence for a direct relationship between thyroid status and (Ca++)i homeostasis in human PMNs, mainly related to direct actions of TSH and T4 on these cells.

Intracellular calcium changes induced by the endozepine triakontatetraneuropeptide in human polymorphonuclear leukocytes: role of protein kinase C and effect of calcium channel blockers

Cell communication and signaling : CCS, 2004

The endozepine triakontatetraneuropeptide (TTN) induces intracellular calcium ([Ca ++ ] i ) chang... more The endozepine triakontatetraneuropeptide (TTN) induces intracellular calcium ([Ca ++ ] i ) changes followed by activation in human polymorphonuclear leukocytes (PMNs). The present study was undertaken to investigate the role of protein kinase (PK) C in the modulation of the response to TTN by human PMNs, and to examine the pharmacology of TTN-induced Ca ++ entry through the plasma membrane of these cells.

Scanning electron microscopy examination of endothelium morphology in human carotid plaques

Micron (Oxford, England : 1993), 2010

Angiotensin II type 1 receptor expression in polymorphonuclear leukocytes from high-risk subjects: changes after treatment with simvastatin

Journal of cardiovascular pharmacology, 2007

Statins may directly interfere with the effects of angiotensin (Ang) II, which is a key player in... more Statins may directly interfere with the effects of angiotensin (Ang) II, which is a key player in the pathogenesis of atherosclerosis (ATH). Ang II promotes a wide array of detrimental processes including a prominent proinflammatory effect, increasingly regarded as a target for therapeutic intervention. Because the proinflammatory effects of Ang II are exerted mainly through the activation of Ang II type 1 receptors (AT1Rs) the present study was devised to investigate by means of real-time polymerase chain reaction (PCR) and flow cytometry techniques the expression of such receptors on circulating polymorphonuclear leukocytes (PMNs) from subjects at high risk for vascular events before and during treatment with simvastatin and in sex- and age-matched healthy controls. In vitro experiments were also performed to assess the ability of simvastatin to interfere with Ang II signaling in human PMNs. In comparison to controls, high-risk subjects had similar AT1R expression on the cell membranes but significantly higher AT1R messenger ribonucleic acid (mRNA) levels. Treatment of high-risk subjects with simvastatin for 30 days resulted in a reduction of AT1R mRNA down to the levels of cells from healthy subjects. In vitro, Ang II-induced activation of the guanosine triphosphate (GTP)-binding protein Rac 1 in human PMNs was inhibited by simvastatin. In conclusion, simvastatin induces downregulation of AT1R expression, interferes with Ang II activity in PMNs, and contributes to the antiinflammatory profile of statins that can explain the therapeutic effects of these drugs.

Neutrophils and clinical outcomes in patients with acute coronary syndromes and/or cardiac revascularisation. A systematic review on more than 34,000 subjects

Thrombosis and haemostasis, 2011

Some studies have suggested that high levels of total white blood cell (WBC) count and C-reactive... more Some studies have suggested that high levels of total white blood cell (WBC) count and C-reactive protein (CRP) may be considered as independent prognostic factors in patients with acute coronary syndromes (ACS) and/or after cardiac revascularisation by percutaneous coronary intervention or coronary artery bypass grafting surgery. Evidence on the role of neutrophils in cardiovascular disease is less compelling. Therefore, we conducted a systematic review of the literature with the aim of identifying all the available evidence to clarify the role of neutrophils (absolute or relative count, neutrophil/lymphocyte ratio) as a prognostic risk factor in patients with ACS and/or cardiac revascularisation. All published studies evaluating the role of neutrophils as a risk factor for clinical outcomes were assessed using the MEDLINE and EMBASE databases. Study selection, data extraction and validity assessment was performed independently by two reviewers. Twenty-one studies (17 of which had positive results) for a total of more than 34,000 patients were included. Ten of 13 studies in ACS patients found that neutrophils measured on-admission are related to mortality rate and/or to major adverse clinical events. A predictive value of neutrophils after cardiac revascularisation procedures was reported in seven out of eight studies. Most of the studies showed that neutrophils were independent predictors of cardiovascular outcomes when analysed concomitantly with other markers of inflammation (WBC, CRP). The findings of our systematic review highlight the potential application of this inexpensive and readily available inflammatory marker for risk stratification in patients with ACS and/or cardiac revascularisation.

Simvastatin treatment in subjects at high cardiovascular risk modulates AT1R expression on circulating monocytes and T lymphocytes

Journal of hypertension, 2008

Angiotensin II, through the activation of angiotensin II type 1 receptors, plays a crucial role i... more Angiotensin II, through the activation of angiotensin II type 1 receptors, plays a crucial role in atherosclerosis. Statins may interfere with the effects of angiotensin II. We have investigated the expression of angiotensin II type 1 receptor, angiotensin II type 2 receptor and angiotensinogen on circulating monocytes and T-lymphocytes from subjects at high risk for vascular events before and during simvastatin treatment, and healthy controls. In-vitro experiments were also performed to assess the ability of simvastatin to interfere with angiotensin II signalling. In comparison with controls, high-risk subjects had similar angiotensin II type 1 receptor expression on the cell membranes but significantly higher angiotensin II type 1 receptor mRNA levels at least in monocyte subsets whereas their expression on T cells was similar. Angiotensin II type 2 receptor mRNA expression was higher than controls in both monocytes and T lymphocytes. No differences were observed in angiotensinogen expression on monocytes while T lymphocytes of high-risk subjects show higher expression. One-month treatment of high-risk subjects with simvastatin resulted in a reduction of angiotensin II type 1 receptor mRNA without affecting angiotensin II type 2 receptor whereas angiotensinogen mRNA expression was reduced at least in monocytes. Incubation in vitro with simvastatin reduces the expression of angiotensin II type 1 receptor mRNA levels on monocytes from untreated subjects. Simvastatin induces down-regulation of the angiotensin II type 1 receptor, interferes with angiotensin II activity in immune cells and contributes to the anti-inflammatory profile of statins that can explain the therapeutic effects of these drugs.

Diazepam-binding inhibitor-derived peptides induce intracellular calcium changes and modulate human neutrophil function

Journal of leukocyte biology, 2000

We studied the effects of two diazepambinding inhibitor (DBI)-derived peptides, triakontatetraneu... more We studied the effects of two diazepambinding inhibitor (DBI)-derived peptides, triakontatetraneuropeptide (DBI 17-50, TTN) and eiksoneuropeptide (DBI 51-70, ENP), on cytosolic free Ca 2؉ concentrations ([Ca 2؉ ] i ), chemotaxis, superoxide anion (O 2 Ϫ ) generation, and phagocytosis in human neutrophils. Both TTN and ENP induced a rapid and transient rise of [Ca 2؉ ] i . The effect of TTN depended on the presence of extracellular Ca 2؉ , whereas the effect of ENP also persisted after extracellular Ca 2؉ chelation. TTN induced neutrophil chemotaxis, stimulated O 2 Ϫ generation, and enhanced phagocytosis. ENP did not affect cell migration and oxidative metabolism but enhanced phagocytosis. Both peptides modulated N-formylmethionyl-leucyl-phenylalanine-and phorbol myristate acetate-induced O 2 ؊ generation. Because neutrophils express benzodiazepine receptors of the peripheral type (pBRs) and DBI-derived peptides may interact with such receptors, we investigated the possible role of pBRs in TTN-or ENPinduced effects. The synthetic pBR ligand RO

Laminar pattern of mineral calcium-phosphorus deposits in a human carotid plaque: nanoscale ultrastructure and elemental analysis

Circulation, 2010

Images in cardiovascular medicine. Scanning electron microscopy examination and elemental analysis of atherosclerotic calcifications in a human carotid plaque

Circulation, 2008

Angiotensin type 1 receptor expression and interleukin-8 production in polymorphonuclear leukocytes of patients with peripheral arterial disease

Journal of cardiovascular pharmacology, 2009

We investigated angiotensin type 1 receptor (AT1R) expression and interleukin-8 (IL-8) production... more We investigated angiotensin type 1 receptor (AT1R) expression and interleukin-8 (IL-8) productions in polymorphonuclear leukocytes obtained from patients with peripheral arterial disease (PAD) undergoing femoral endarterectomy. Subjects at high cardiovascular risk (high-risk subjects, HRS) and healthy controls (HC) were also enrolled. To this end, patients with PAD were studied 1 month before surgery, at the time of surgery, and 3 and 6 months after surgery. Polymorphonuclear leukocytes were obtained from venous blood and evaluated for AT1R expression at messenger RNA (mRNA) and protein level and IL-8 production (by means of enzyme-linked immunosorbent assay). At baseline, AT1R membrane expression was similar in cells from patients with PAD, HRS, and HC, whereas AT1R mRNA was similar in patients with PAD and HC and higher in HRS. During the follow-up period, AT1R expression progressively decreased both on the cell membrane and at the mRNA level. Both resting and stimulated production of IL-8 was lower in patients with PAD in comparison to HC and HRS and did not change during the follow up period. In PAD patients, femoral endarterectomy is associated with reduction of AT1R expression however with no apparent effect on IL-8 production. The relevance of such effects for cardiovascular protection deserves consideration.

Pain perception, blood pressure levels, and peripheral benzodiazepine receptors in patients followed for differentiated thyroid carcinoma: a longitudinal study in hypothyroidism and during hormone treatment

The Clinical journal of pain

Elevated blood pressure levels that are associated with hypalgesia and hypothyroidism have major ... more Elevated blood pressure levels that are associated with hypalgesia and hypothyroidism have major influences on the cardiovascular system. The potential modulation of pain sensitivity by thyroid hormones is largely undetermined. Moreover, a few experimental studies show that peripheral benzodiazepine receptors (PBRs), which may be altered in hypothyroidism, seem to be related with pain perception. Dental pain threshold and tolerance were evaluated in 19 patients followed for differentiated thyroid carcinoma (1) in severe short-term hypothyroidism (phase 1) and (2) during thyroid stimulating hormone-suppressive LT4 treatment (phase 2). PBR expression (cytofluorimetric evaluation) on peripheral blood mononuclear cells was also investigated in the 2 phases. Pain perception differed throughout the study, the dental pain threshold was higher in phase 1 (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) whereas pain tolerance was higher but not significantly (P=0.07). Although the systolic blood pressure was higher during hypothyroidism (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01), no relationship was found between blood pressure changes and pain sensitivity variations. Moreover, the multiple regression analysis showed an independent association of the clinical phase with pain sensitivity (r=-2.61, P=0.029), while accounting for systolic blood pressure. The intensity of PBRs was significantly higher in the first phase of the study (P=0.047) whereas the ratio did not significantly differ. However, no relationship was observed between pain sensitivity and PBRs. In conclusion, in athyreotic patients, the pain sensitivity is related to the thyroid status and is independent of the increase in blood pressure induced by thyroid hormone deprivation. The PBRs do not seem to have major influence on pain sensitivity changes in hypothyroidism.

Changes in autonomic modulation to the heart and intracellular catecholamines. A longitudinal study in differentiated thyroid carcinoma during short-term hypothyroidism and thyroid hormone replacement

Hormone research, 2007

band (p = 0.052). The baroreflex gain ␣ LF index was similar in the two phases. The stimulus-indu... more band (p = 0.052). The baroreflex gain ␣ LF index was similar in the two phases. The stimulus-induced cellular production of norepinephrine and epinephrine in peripheral blood mononuclear cells was significantly higher in phase 2. Conclusion: The neurally-mediated influences on the sinus node and the study of intracellular catecholamine production suggest a reduced sympathoexcitation in hypothyroidism. The early increase in blood pressure observed after thyroid hormone withdrawal is not due to impaired sensitivity of the baroreflex arc.

Adrenergic mechanisms in the control of gastrointestinal motility: from basic science to clinical applications

Pharmacology & therapeutics, 1996

Over the years, a vast literature has accumulated on the adrenergic mechanisms controlling gut mo... more Over the years, a vast literature has accumulated on the adrenergic mechanisms controlling gut motility, blood flow, and mucosal transport. The present review is intended as a survey of key information on the relevance of adrenergic mechanisms modulating gut motility and will provide an outline of our knowledge on the distribution and functional role of adrenoceptor subtypes mediating motor responses. aI-Adrenoceptors are located postsynaptically on smooth muscle cells and, to a lesser extent, on intrinsic neurons; cr,-adrenoceptors may be present both pre-and postsynaptically, with presynaptic auto-and hetero-receptors playing an important role in the modulation of neurotransmitter release; @-adrenoceptors are found mainly on smooth muscle cells. From a clinical standpoint, adrenoceptor agonists/antagonists have been investigated as potential motility inhibiting (antidiarrheallantispasmodic) or prokinetic agents, although at present their field of application is limited to select patient groups. PHARMACOL THER 69(l): 59-78, 1996.

Components of arterial systolic pressure and RR-interval oscillation spectra in a case of baroreflex failure, a human open-loop model of vascular control

Journal of human hypertension, 2010

The baroreflex control of circulation is always operating and modulates blood pressure and heart ... more The baroreflex control of circulation is always operating and modulates blood pressure and heart rate oscillations. Thus, the study of cardiovascular variability in humans is performed in a closed-loop model and the physiology of post-sinoaortic denervation is completely unknown in humans. We dissected for the first time the different components of systolic arterial pressure (SAP) and RR-interval spectra in a patient with 'baroreflex failure' (due to mixed cranial nerve neuroma) who represents a human model to investigate the cardiovascular regulation in an open-loop condition. Interactions among cardiovascular variability signals and respiratory influences were described using the multivariate parametric ARXAR model with the following findings:

Lack of relationship between cardiovascular reactivity to mental stress and autonomic modulation of the sinoatrial node in normotensive and hypertensive male subjects

International journal of psychophysiology : official journal of the International Organization of Psychophysiology, 2009

A cardiovascular over-reactivity to stress may participate in the pathophysiology of hypertension... more A cardiovascular over-reactivity to stress may participate in the pathophysiology of hypertension. The aim of this study was to investigate whether baseline indexes of autonomic modulation of heart rate or baroreflex sensitivity were correlated with cardiovascular reactivity to stress. Spectral parameters of RR interval variability and the LFalpha-index were calculated in a resting condition in 53 untreated subjects (34 hypertensives; 19 normotensives). The reactivity to stress was expressed as changes of mean RR and systolic blood pressure during arithmetic mental stress testing. The cardiovascular reactivity was not correlated with either baseline spectral parameters of RR interval variability or LFalpha-index. In the multivariate analysis no confounding effect of diagnosis (hypertension vs normotension) was found. Moreover no interaction between diagnosis and both LF/HF ratio and LFalpha-index was observed. Thus, the cardiovascular response to a mental stimulus appears to prevail over the baseline pattern of cardiovascular regulation independently of the presence or absence of the hypertensive disease.

Glossary for Academic Integrity (revised version)

by Loreta Tauginiene and Marco Cosentino

This report serves as a basis to further common understanding on academic integrity through learn... more This report serves as a basis to further common understanding on academic integrity through learning new terms and rediscovering old terms in new contexts. The need for this document derives from the variety of terms that are commonly used, but under different contexts. In this sense, we attempted to arrive at a common meaning.
This report could be of value to national ombudspersons, judicial authorities, compliance officers, research project managers and other related bodies or units in academia as well as students, business sector and others.

Glossary for Academic Integrity

by Loreta Tauginiene, Inga Gaizauskaite, julius kravjar, Milan Ojsteršek, and Marco Cosentino

This report serves as a basis to further common understanding on academic integrity through learn... more This report serves as a basis to further common understanding on academic integrity through learning new terms and rediscovering old terms in new contexts. The need for this document derives from the variety of terms that are commonly used, but under different contexts. In this sense, we attempted to arrive at a common meaning.
This report could be of value to national ombudspersons, judicial authorities, compliance officers, research project managers and other related bodies or units in academia as well as students, business sector and others.

Effects of a novel cyclic RGD peptidomimetic on cell proliferation, migration and angiogenic activity in human endothelial cells

by Mayra Paolillo, L. Schembri, Umberto Piarulli, and Marco Cosentino

Cyclic RGD peptidomimetics containing a bifunctional diketopiperazine scaffold are a novel class ... more Cyclic RGD peptidomimetics containing a bifunctional diketopiperazine scaffold are a novel class of high-affinity ligands for the integrins αVβ3 and αVβ5. Since integrins are a promising target for the modulation of normal and pathological angiogenesis, the present study aimed at characterizing the ability of the RGD peptidomimetic cyclo[DKP-RGD] 1 proliferation, migration and network formation in human umbilical vein endothelial cells (HUVEC). Cell viability was assessed by flow cytometry and annexin V (ANX)/propidium iodide (PI) staining. Cell proliferation was evaluated by the ELISA measurement of bromodeoxyuridine (BrdU) incorporation. Network formation by HUVEC cultured in Matrigel-coated plates was evaluated by optical microscopy and image analysis. Integrin subunit mRNA expression was assessed by real time-PCR and Akt phosphorylation by western blot analysis. Cyclo[DKP-RGD] 1 does not affect cell viability and proliferation either in resting conditions or in the presence of the pro-angiogenic growth factors VEGF, EGF, FGF, and IGF-I. Addition of cyclo[DKP-RGD] 1 however significantly decreased network formation induced by pro-angiogenic growth factors or by IL-8. Cyclo[DKP-RGD] 1 did not affect mRNA levels of αV, β3 or β5 integrin subunits, however it significantly reduced the phosphorylation of Akt. Cyclo[DKP-RGD] 1 can be a potential modulator of angiogenesis induced by different growth factors, possibly devoid of the adverse effects of cytotoxic RGD peptidomimetic analogues.

Levodopa-Induced Neutropenia

by Christian Cordano, Maria Cellerino, Angelo Schenone, and Marco Cosentino

Parkinsonism & Related Disorders, 2015

Strong activation of dopamine pathway in synovial tissue from rheumatoid arthritis patients: new target of pathology? [abstract]

post-visit [IFNg: 0.4, p = .044; IL-10: 0.32 p = .021; IL-12: 0.45, p = .030; IL1b: 0.38, p = .03... more post-visit [IFNg: 0.4, p = .044; IL-10: 0.32 p = .021; IL-12: 0.45, p = .030; IL1b: 0.38, p = .033; IL2: 0.45, p = .030; IL4: 0.48, p = .028; IL5: 0.32 p = .027]. Findings suggest that follow-up visits trigger cognitive processes that may cause women to reflect on their cancer experience longer than previously thought (influencing immunity), despite reporting decreased uncertainty and anxiety after receiving good news. This study supports the need for additional longitudinal research to evaluate associations between, and moderators (e.g. trait anxiety; the patient-provider relationship) of emotional distress and immunity surrounding follow-up care for breast cancer survivors.

Variazioni circadiane di citochine e cortisolo in bambini con OSAS

... Luana Nosetti1, Michela Gaiazzi1, Alessandra Cristina Niespolo1, Ramona Consuelo Maio2, Franc... more

Levodopa-Induced Neutropenia

Two cases of hepatotoxicity following high-doses methylprednisolone therapy for demyelinating diseases

Elementi essenziali di farmacocinetica

Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting α v β 3 Integrin and VEGF Receptors

by Alberto Dal Corso and Marco Cosentino

ChemistryOpen, 2015