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Pubblicazioni scientifiche indicizzate su Pub Med

1. Expert Opin Drug Metab Toxicol. 2011 Jan;7(1):39-47. Epub 2010 Dec 11.

Gene polymorphisms involved in triptans pharmacokinetics and pharmacodynamics in
migraine therapy.

Gentile G, Borro M, Simmaco M, Missori S, Lala N, Martelletti P.

Sapienza University, 2nd School of Medicine, Advanced Molecular Diagnostic Unit,
Department of Biochemical Sciences, Rome, Italy.

IMPORTANCE OF THE FIELD: Migraine is a debilitating and painful neurological
disorder affecting millions of people worldwide and often worsened by
chronification. Triptans represent a powerful pharmacological resource in
migraine management; nevertheless, a significant portion of treated patients do
not obtain consistent pain relief through triptans. Pharmacogenomics may offer a
new way to rationalise triptans administration, based on characterisation of the
individual genomic profile.
AREAS COVERED IN THIS REVIEW: The review summarises the results of association
studies between polymorphisms in genes involved in the kinetics and dynamics of
triptans, and clinical response to them in migraineurs.
WHAT THE READER WILL GAIN: A summary of data available at present from genetic
studies in the field of triptan therapy in migraine, and a picture of the
difficulties facing research into the pharmacogenomics of triptans.
TAKE HOME MESSAGE: Pharmacogenomic studies of triptans suggest that some genetic
determinants influence drug response, but the complexity of the field calls for
application of a systematic approach to genetic association studies, allowing
identification of a therapy response prediction panel with adequate predictive
power.

PMID: 21142809 [PubMed – indexed for MEDLINE]

2. J Headache Pain. 2010 Oct;11(5):431-5. Epub 2010 Jul 22.

Genetic polymorphisms related to efficacy and overuse of triptans in chronic
migraine.

Gentile G, Borro M, Lala N, Missori S, Simmaco M, Martelletti P.

Department of Biochemical Sciences, Advanced Molecular Diagnostic Unit, 2nd
School of Medicine, Sant’Andrea Hospital, Sapienza University of Rome, Via di
Grottarossa 1035, Rome, Italy. giovanna.gentile@uniroma1.it

Migraine is a common type of headache and its most severe attacks are usually
treated with triptans, the efficacy of which is extremely variable. Several SNPs
in genes involved in metabolism and target mechanisms of triptans have been
described. To define an association between genetic profile and triptan response,
we classified a migrainous population on the basis of triptan response and
characterized it for polymorphisms in the genes coding for monoamine oxidase A, G
protein β3 and the cytochrome CYP1A2. Analysis of the association between
genotypic and allelic frequencies of the analyzed SNPs and the grade of response
to triptan administration showed a significant correlation for MAOA uVNTR
polymorphism. Further stratification of patients in abuser and non-abuser groups
revealed a significant association with triptan overuse and, within the abusers,
with drug response to the CYP1A2*1F variant.

PMID: 20652353 [PubMed – indexed for MEDLINE]

3. J Headache Pain. 2010 Apr;11(2):151-6. Epub 2010 Mar 6.

Frequencies of genetic polymorphisms related to triptans metabolism in chronic
migraine.

Gentile G, Missori S, Borro M, Sebastianelli A, Simmaco M, Martelletti P.

Department of Biochemical Sciences, Advanced Molecular Diagnostic Unit, 2nd
School of Medicine, Sapienza University, Sant’Andrea Hospital, Via di Grottarossa
1035, Rome, Italy.

Chronic migraine (CM) prevalence ranges around 1-5%. Most of these patients
usually treat their acute attacks with triptans, whose efficacy is extremely
variable. A genetic basis for migraine is evident and many susceptibility genes
have been described, as well as gene polymorphisms possibly implied in therapy
response. Several factors could be involved in the evolution of episodic migraine
into a chronic form, such as natural history, psychiatric comorbidity, and the
individual’s response to therapy. During a study aimed at detecting connections
between genotype and response to triptans administration, we characterized a CM
population for polymorphisms in the genes coding for monoamine oxidase A,
g-protein beta 3 and the cytochromes CYP3A4 and CYP1A2. Alleles and genotypes
distributions were compared with known frequencies of healthy Caucasian
populations. A significant association with CM was found for the long allele of
monoamine oxidase A 30 bp VNTR and CYP1A2*1F variant. Such genomic analysis is
part of an integrated platform able to evaluate different levels of metabolic
pathways of drugs in CM and their influence in the chronicization process.

PMID: 20213484 [PubMed – indexed for MEDLINE]

4. Expert Rev Neurother. 2009 Sep;9(9):1267-9.

Pharmacogenomics in migraine: catching biomarkers for a predictable disease
control.

Simmaco M, Borro M, Missori S, Martelletti P.

Erratum in
Expert Rev Neurother. 2009 Nov;9(11):1706.

PMID: 19769441 [PubMed – indexed for MEDLINE]

5. Intern Emerg Med. 2009 Oct;4(5):367-73. Epub 2009 Jun 24.

Future drugs for migraine.

Farinelli I, De Filippis S, Coloprisco G, Missori S, Martelletti P.

Department of Medical and Molecular Sciences, Regional Referral Headache Centre,
II School of Medicine, Sapienza University of Rome, Sant’Andrea Hospital, Via di
Grottarossa 1039, 00189 Rome, Italy.

Migraine is a complex, neurovascular disorder in which genetic and environmental
factors interact. At present, frontline therapies in the acute treatment of
migraine include the use of non-steroidal anti-inflammatory drugs and triptans.
Evidence indicates that calcitonin gene-related peptide (CGRP) plays a
fundamental role in the mechanism of migraine. CGRP is a strong vasodilatatory
neuropeptide that is released from activated trigeminal sensory nerves. The
development of CGRP antagonists has also been driven by the fact that triptans
are vasoconstrictive and cannot be safely used in patients with cardiovascular
risk factors. Olcegepant (BIBN4096) is the first CGRP antagonist for the
treatment of migraine that has been tested in clinical trials, but because of its
poor oral bioavailability, only the intravenous formulation has been tested. The
first oral non-peptide CGRP antagonist, telcagepant, has been shown recently to
be highly effective in the treatment of migraine attacks. This development can be
considered as the most important pharmacological breakthrough for migraine
treatment since the introduction of sumatriptan in the early 1990s. These results
are also of importance, since they support an interesting pathophysiological
hypothesis of migraine. The pipeline of future compounds for the treatment of
acute migraine headaches include TPRV1 antagonists, prostaglandin E receptor 4
(EP(4)) receptor antagonists, serotonin 5HT1(F) receptor agonists and nitric
oxide synthase inhibitors. The immediate future of a preventative treatment for
migraine headaches is well represented by botulinum toxin type-A, glutamate NMDA
receptor antagonists, gap-junction blocker tonabersat and an angiotensin type 1
blocker candesartan.

PMID: 19551474 [PubMed – indexed for MEDLINE]

6. Expert Rev Neurother. 2008 Sep;8(9):1347-54.

Proinflammatory mediators and migraine pathogenesis: moving towards CGRP as a
target for a novel therapeutic class.

Farinelli I, Missori S, Martelletti P.

Department of Medical Sciences, 2nd School of Medicine, Sapienza University,
Sant’Andrea Hospital, Via di Grottarossa 1035, I-00189 Rome, Italy.
ivano.farinelli@uniroma1.it

Migraine is a complex neurological disorder in which genetic and environmental
factors interact. At present, frontline therapies in migraine’s acute treatment
include the use of NSAIDS and triptans. Restrictions in the use of frontline
drugs for migraine treatment and evidence concerning CGRP’s key role led research
towards new pathways involved in migraine pathophysiology. CGRP is a strong
vasodilatory neuropeptide released from activated trigeminal sensory nerves. The
development of CGRP antagonists has also been driven by the fact that triptans
are vasoconstrictive and cannot be used in patients with vascular risk factors.
BIBN4096 (olcegepant) is the first CGRP antagonist for the treatment of migraine
which has been tested in clinical trials, but its principal limitation is that
BIBN4096 presents low oral bioavailability and has only been tested through
intravenous formulation. The first oral nonpeptide CGRP antagonist, MK-0974
(telcagepant), has recently been shown to be highly effective in the treatment of
migraine attacks. This development can be considered the most important
pharmacological breakthrough for migraine treatment since the introduction of
sumatriptan in the early 1990s. These results are important since they confirm
the current pathophysiological concept of migraine. The future introduction of
CGRP antagonists in clinical practice could represent a progress for migraine
therapy.

PMID: 18759547 [PubMed – indexed for MEDLINE]

7. Nutr Metab Cardiovasc Dis. 2008 Nov;18(9):585-95. Epub 2007 Dec 3.

The Italian Diabetes and Exercise Study (IDES): design and methods for a
prospective Italian multicentre trial of intensive lifestyle intervention in
people with type 2 diabetes and the metabolic syndrome.

Balducci S, Zanuso S, Massarini M, Corigliano G, Nicolucci A, Missori S, Cavallo
S, Cardelli P, Alessi E, Pugliese G, Fallucca F; Italian Diabetes Exercise Study
(IDES) Group.

Collaborators: Pugliese G, Nicolucci A, Mungra P, Zanuso S, Balducci S, Balducci
G, Benvenuti P, Cardelli P, Cavallo S, Simmaco M, Borro M, Gentile G, Massarini
M, Letizia C, Pugliese G, Fallucca F, Pugliese G, Missori S, Ribaudo MC, Alessi
E, Strollo F, Morè M, Alimonti P, Di Biase N, Lasaracina F, Santantonio G,
Cruciani L, Manunta M, Di Mauro M, Sesti G, Irace C, Puccio L, Cignarelli M,
Nicastro V, Piemontese S, Corigliano G, Rossi E, Corigliano M, De Feo P, Fatone
C, Baggiore C, Russo CR, Boemi M, Lanari L, Valentini U, Girelli A, Zarra E, Di
Bartolo P, Pellicano F, Mazzuca P, Manicardi E, Bruno A, Romano L, Sambataro M,
Balducci S, Pontiroli A, Laneri M, Boggio A, Zagari N, Fernando F, Iacobini C,
Milo L, Balducci G, Senigagliesi L, Spinelli E, Di Giovanni A, Pineda M, Pandolfo
U, De Fazio CG, Settequattrini A, Gambacciani A, Gambacciani M, Fabrizi M,
Ceccherini A, Balducci E, Quattrini M, Massarini M, Baggio G, Fornari M, Violi D,
Cherubini G, Mastelloni F, Micali V, Cilano D, Di Luciano S, Canevari D.

Metabolic Fitness Association, Monterotondo, Rome, Italy. sbalducci@esinet.it

BACKGROUND AND AIMS: The IDES is a prospective Italian multicentre randomized
controlled trial to evaluate the efficacy of an intensive lifestyle intervention
on modifiable cardiovascular disease (CVD) risk factors in a large cohort of
people with type 2 diabetes and the metabolic syndrome.
METHODS AND RESULTS: We recruited 606 subjects with type 2 diabetes and waist
circumference >94 cm (M) and >80 cm (F), plus >1 other metabolic syndrome trait
(IDF criteria) for both sexes, aged 40-75 years, BMI 27-40 kg/m(2), diabetes
duration >1 year with a sedentary lifestyle of >6 months. Patients were
randomized into two groups: a control group, receiving conventional care
including exercise counselling and an intervention group, treated with a mixed
(aerobic and resistance) exercise programme (150 min/week) prescribed and
supervised for 12 months. Primary outcome is HbA1c reduction. Secondary outcomes
include other traditional and non-traditional risk factors and their relationship
to exercise volume/intensity and fitness; dosage of glucose, lipid and blood
pressure-lowering drugs; global CVD 10-year risk; patient well-being; and costs.
CONCLUSION: This trial verifies whether a prescribed and supervised exercise
programme, including both aerobic and resistance training, is more effective than
conventional exercise counselling in reducing modifiable CVD risk factors in type
2 diabetic subjects with the metabolic syndrome.

PMID: 18061415 [PubMed – indexed for MEDLINE]

8. J Am Soc Nephrol. 2003 Aug;14(8 Suppl 3):S264-70.

Role of galectin-3 in diabetic nephropathy.

Iacobini C, Amadio L, Oddi G, Ricci C, Barsotti P, Missori S, Sorcini M, Di Mario
U, Pricci F, Pugliese G.

Laboratory of Metabolism and Pathological Biochemistry, Section of Endocrine
Biochemistry, Istituto Superiore di Sanità, Rome, Italy.

The advanced glycosylation end products (AGE) participate in the pathogenesis of
nephropathy and other diabetic complications through several mechanisms,
including their binding to cell surface receptors. The AGE receptors include
RAGE, the macrophage scavenger receptors, OST-48 (AGE-R1), 80K-H (AGE-R2), and
galectin-3 (AGE-R3). Galectin-3 interacts with the beta-galactoside residues of
cell surface and matrix glycoproteins via the carbohydrate recognition domain and
with intracellular proteins via peptide-peptide associations mediated by its
N-terminus domain. These structural properties enable galectin-3 to exert
multiple functions, including the mRNA splicing activity, the control of cell
cycle, the regulation of cell adhesion, the modulation of allergic reactions, and
the binding of AGE. The lack of transmembrane anchor sequence or signal peptide
suggests that it is associated with other AGE receptors, possibly AGE-R1 and
AGE-R2, to form an AGE-receptor complex, rather than playing an independent role.
In target tissues of diabetic vascular complications, such as the endothelium and
mesangium, galectin-3 is weakly expressed under basal conditions and is markedly
upregulated by the diabetic milieu (and to a lesser extent by aging).
Galectin-3-deficient mice were found to develop accelerated diabetic
glomerulopathy versus the wild-type animals, as evidenced by the more pronounced
increase in proteinuria, mesangial expansion, and matrix gene expression. This
was associated with a more marked renal/glomerular AGE accumulation, suggesting
that it was attributable to the lack of galectin-3 AGE-receptor function. These
data indicate that galectin-3 is upregulated under diabetic conditions and is
operating in vivo to provide protection toward AGE-induced tissue injury, as
opposed to RAGE.

PMID: 12874444 [PubMed – indexed for MEDLINE]

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