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LUIGI ALBERTO PINI

CULTORE DELLA MATERIA
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede Policlinico

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Pubblicazioni

2021 - Diagnostic proteomic biomarkers to detect kidney diseases [Abstract in Rivista]
Ozben, Tomris; Bellei, Elisa; Monari, Emanuela; Bergamini, Stefania; Pini, Luigi Alberto; Tomasi, Aldo
abstract

Urinary proteomics is primarily applied to the study of renal and urogenital tract disorders. Here are reported two distinct successful examples of this approach for the discovery of early urinary biomarkers of kidney­ related dysfunctions: diabetic nephropathy (DN), a well ­known complication of diabetes frequently leading to dialysis, and drug­induced nephrotoxicity, a possible condition caused by medication ­overuse headache (MOH). Early detection of kidney disorders based on selective biomarkers could permit to diagnose patients at the initial stage of the disease, where the therapy is still possible to stop or prevent occurrence of advance disease. Urine samples were first concentrated and desalted. Subsequently, they were subjected to two­-dimensional gel electrophoresis (2­DE) coupled to mass spectrometry (MS) for protein identification. Furthermore, some proteins were verified by Western blot and ELISA test. In diabetes-­related study, 11 differentially expressed proteins were detected (8 up­regulated and 3 down­regulated) in type 2 diabetic (T2D) and T2DN patients compared to the healthy control subjects. In MOH study, a total of 21 over­excreted proteins was revealed in urine of non­-steroidal anti­inflammatory drugs (NSAIDs) and mixtures abusers vs controls. Particularly, 4 proteins were positively validated by immunoblotting and ELISA. Urinary proteomics allows non­invasive assessment of renal diseases at an early stage by the identification of characteristic protein pattern.

2020 - A case-control study of visually evoked postural responses in childhood with primary headaches [Articolo su rivista]
Baraldi, C; Gherpelli, C; Alicandri Ciufelli, M.; Monzani, D.; Pini, L. A.; Pani, L.; Guerzoni, S.
abstract

Background: Disorientation, nausea, confusion, dizziness, and displacement are frequently complained by headache-suffering children. Anyhow, the cause of these symptoms is still unclear, and a dysfunction of vestibular pathways or their alteration due to central pain pathways hyper-activation, has been proposed. The aim of this study is to use posturography to explore the balance function of headache-suffering children during pain-free periods. Methods: Posturography was performed on 19 migraineurs, 11 tension-type headache sufferers, and 20 healthy controls. Posturographic measures were performed during headache-free periods under different conditions: with eyes opened, eyes closed, and during right and left optokinetic stimulation. The last 2 conditions were used to mimic unreliable visual signals that can confound vestibular system. Results: During eyes-closed conditions, headache-suffering children displayed higher displacements than healthy controls, since statokinesiogram surface was higher in tension-type headache sufferers and migraineurs compared with controls (P value = 0.0095). Romberg’s index, indicating the overall stability of the subject, was lower in healthy controls than in headache sufferers (P = 0.0139), thus suggesting a vestibular impairment in the seconds. Moreover, both during right and left optokinetic stimulation, the statokinesiogram length was higher in headache-suffering children (P < 0.0001). Thereafter, statokinesiogram surface was higher in migraineurs during right optokinetic stimulation (P = 0.0388) than in tension-type headache sufferers when stimulation was directed on the opposite side (P = 0.0249). Conclusions: These results suggest a central alteration of vestibular pathways in headache-suffering children, that makes balance function more dependent from visual inputs than healthy subjects, even in inter-ictal phases.

2020 - Identification of candidate proteomic markers in the serum of medication overuse headache patients: An exploratory study [Articolo su rivista]
Pellesi, Lanfranco; Guerzoni, Simona; Baraldi, Carlo; Cainazzo, Maria Michela; Pini, Luigi Alberto; Bellei, Elisa
abstract

The pathophysiological mechanism of medication overuse headache is uncertain; no distinctive markers have been described right now. The aim of this study was to conduct proteomic analyses on serum samples from patients with medication overuse headache and healthy individuals. Specifically, mono- (SDS-PAGE) and two-dimensional gel electrophoresis (2-DE) followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) were used to evaluate changes in serum proteins.

2019 - Exploration of candidate serum biomarkers potentially related to the chronic pain condition in Medication-overuse headache [Articolo su rivista]
Pellesi, Lanfranco; Bellei, Elisa; Guerzoni, Simona; Michela Cainazzo, Maria; Baraldi, Carlo; Monari, Emanuela; Pini, Luigi Alberto
abstract

Background Medication Overuse Headache (MOH) is a prevalent and disabling disorder resulting from the overuse of analgesic drugs, triptans or other acute headache medications. In previous proteomic studies, several proteins have been found at high concentrations in the urine of MOH patients and in the serum of rats with neuropathic pain. The aim of this study was to compare the serum levels of lipocalin-type Prostaglandin D2 synthase (L-PGDS), Vitamin D-binding protein (VDBP), apolipoprotein E (APOE) and apolipoprotein A1 (APOA1) in MOH patients and healthy individuals, further exploring their relationship with cutaneous pain thresholds (CPTs) in the territories innervated by the trigeminal nerve. Methods 69 MOH patients and 42 age- and sex-matched healthy volunteers were enrolled in the study. Von Frey-like filaments were applied to the skin territories innervated by the trigeminal nerve, to determine the CPTs. L-PGDS, VDBP, APOE and APOA1 were quantified in the serum by Enzyme-linked Immunosorbent Assay (ELISA). Clinical and laboratory data were collected. Comparisons between MOH patients and healthy individuals were performed using independent t test or χ2 test. To correlate serum proteins with CPTs, Pearson correlation coefficient or Spearman's rank correlation coefficient were used. Results CPTs were lower among MOH patients. L-PGDS, VDBP and APOE had significantly different serum concentrations between groups (p < 0.01), but no correlation was found with CPTs. APOA1 serum concentrations did not differ between patients and healthy individuals. Conclusions L-PGDS, VDBP and APOE had abnormal serum levels in MOH patients, confirming their alteration in some conditions of chronic headache and neuropathic pain. The in-depth study of target proteins represents a promising approach for a better understanding of MOH, as well as the detection of candidate biomarkers for chronic headache or the risks associated with overuse medications.

2019 - Nabilone administration in refractory chronic diarrhea: A case series [Articolo su rivista]
Pellesi, L.; Verga, M. C.; De Maria, N.; Villa, E.; Pini, L. A.; Guerzoni, S.
abstract

Background: Daily cannabis assumption is currently associated with several physical and mental health problems, however in the past it was prescribed for a multitude of symptoms, including vomiting, abdominal pain and diarrhea. Through the years, the endocannabinoid system has been recognized in the homeostatic mechanisms of the gut, as well as in the physiological control of intestinal motility and secretion. Accordingly, cannabinoids may be a promising therapy against several gastrointestinal conditions, such as abdominal pain and motility-related disorders. Case presentation: We retrospectively analysed the efficacy and safety of a CB1-receptor agonist administered in six patients with refractory chronic diarrhea, between April 2008 and July 2016. After three months of therapy, oral nabilone improved the health of nearly all patients, with visible improvements in reducing diarrheal symptoms and weight gain. Most of the benefits persisted through the three-month follow-up. Only one patient interrupted the treatment after one month, due to severe fatigue and mental confusion; the symptoms disappeared in the follow-up period. Conclusions: These findings encourage the study of cannabinoids acting on CB1 receptors in chronic gastrointestinal disorders, especially in refractory chronic diarrhea, offering a chance for a substantial improvement in the quality of life of selected patients, with a reasonable safety profile.

2019 - Placebo effect between evidence and myths: How to distinguish true from fake news [Capitolo/Saggio]
Vilella, Antonietta; Pini, Luigi Alberto
abstract

2018 - Genetic variation in CHRNA7 and CHRFAM7A is associated with nicotine dependence and response to varenicline treatment [Articolo su rivista]
Cameli, Cinzia; Bacchelli, Elena; De Paola, Maria; Giucastro, Giuliano; Cifiello, Stefano; Collo, Ginetta; Cainazzo, Maria Michela; Pini, Luigi Alberto; Maestrini, Elena; Zoli, Michele
abstract

The role of nicotinic acetylcholine receptors (nAChR) in nicotine dependence (ND) is well established; CHRNA7, encoding the α7 subunit, has a still uncertain role in ND, although it is implicated in a wide range of neuropsychiatric conditions. CHRFAM7A, a hybrid gene containing a partial duplication of CHRNA7, is possibly involved in modulating α7 nAChR function. The aim of this study was to investigate the role of CHRNA7 and CHRFAM7A genetic variants in ND and to test the hypothesis that α7 nAChR variation may modulate the efficacy of varenicline treatment in smoking cessation. We assessed CHRNA7 and CHRFAM7A copy number, CHRFAM7A exon 6 ∆2 bp polymorphism, and sequence variants in the CHRNA7 proximal promoter in an Italian sample of 408 treatment-seeking smokers. We conducted case-control and quantitative association analyses using two smoking measures (cigarettes per day, CPD, and Fagerström Test for Nicotine Dependence, FTND). Next, driven by the hypothesis that varenicline may exert some of its therapeutic effects through activation of α7 nAChRs, we restricted the analysis to a subgroup of 142 smokers who received varenicline treatment. The CHRNA7 promoter variant rs28531779 showed association with both smoking quantitative measures (FNTD p = 0.026, β = 0.89, 95% CI 0.11–1.67; CPD p = 0.006, β = 4.82 95% CI 1.42–8.22). Moreover, in the varenicline-treated subgroup we observed association of CHRFAM7A copy number with 6 months smoking abstinence (p = 0.035, OR = 3.18, 95% CI = 1.09–9.30). Thus, our study points to a possible role of genetic variation in CHRNA7 and CHRFAM7A in tobacco addiction mechanisms and response to varenicline treatment.

2018 - Pharmacokinetics and tolerability of oral cannabis preparations in patients with medication overuse headache (MOH)—a pilot study [Articolo su rivista]
Pellesi, L.; Licata, M.; Verri, P.; Vandelli, D.; Palazzoli, F.; Marchesi, F.; Cainazzo, M. M.; Pini, L. A.; Guerzoni, S.
abstract

Purpose: The recent release of a medical cannabis strain has given a new impulse for the study of cannabis in Italy. The National Health Service advises to consume medical cannabis by vaporizing, in decoction or oil form. This is the first study that explores the pharmacokinetics and tolerability of a single oral dose of cannabis as decoction (200 ml) or in olive oil (1 ml), as a first step to improve the prescriptive recommendations. Methods: This is a single-center, open-label, two-period crossover study designed to assess the pharmacokinetics and tolerability of oral cannabis administered to 13 patients with medication overuse headache (MOH). A liquid chromatography tandem-mass spectrometry (LC-MS/MS) method was conducted for the quantification of THC, CBD, 11-OH-THC, THC-COOH, THC-COOH-glucuronide, THCA-A, and CBDA. Blood pressure, heart rate, and a short list of symptoms by numerical rating scale (NRS) were assessed. Results: Decoctions of cannabis showed high variability in cannabinoids content, compared to cannabis oil. For both preparations, THCA-A and CBDA were the most widely absorbed cannabinoids, while THC and CBD were less absorbed. The most important differences concern the bioavailability of THC, higher in oil (AUC0–24 7.44, 95% CI 5.19, 9.68) than in decoction (AUC0–24 3.34, 95% CI 2.07, 4.60), and the bioavailability of CBDA. No serious adverse events were reported. Conclusions: Cannabis decoction and cannabis oil showed different pharmacokinetic properties, as well as distinct consequences on patients. This study was performed in a limited number of patients; future studies should be performed to investigate the clinical efficacy in larger populations.

2018 - Pharmacological differences and clinical implications of various botulinum toxin preparations: A critical appraisal [Articolo su rivista]
Ferrari, A.; Manca, M.; Tugnoli, V.; Pini, L. A.
abstract

Three different type A botulinum neurotoxins (BoNTAs) — onabotulinumtoxinA, abobotulinumtoxinA and incobotulinumtoxinA) — are currently marketed in Europe to treat several conditions. Differences between BoNTA preparations, which depend on their specific biotypes and manufacturing processes, lead to clinically relevant pharmacotherapeutic dissimilarities. All three available products are separately recognized and reviewed in American Academy of Neurology guidelines. The neurotoxin load/100U is likewise different among the different BoNTAs, with the result that the specific potency of the 150kD BoNTA neurotoxin is calculated as 137 units/ng for onabotulinumtoxinA, 154 units/ng for abobotulinumtoxinA, and 227 units/ng for incobotulinumtoxinA. It is important for clinicians to have all three BoNTAs available in order to choose the most suitable preparation for the specific indication in the single patient. Commercially available BoNTAs must be recognized as different from one another, and therefore as non-interchangeable. The essential experience of the clinician is of the utmost importance in choosing the most appropriate treatment.

2018 - Serum changes of apolipoproteins in Medication Overuse Headache (MOH) [Abstract in Rivista]
Pellesi, Lanfranco; Bellei, Elisa; Baraldi, Carlo; Guerzoni, Simona; Monari, Emanuela; Pini, Luigi Alberto
abstract

Background Medication Overuse Headache (MOH) is a prevalent and disabling disorder resulting from the overuse of analgesic drugs, triptans or other acute headache medications. Previous proteomic studies have identified some altered proteins, including different forms of apolipoproteins, which are probably associated with the chronic painful symptom and its consequences. The aim of the study was to explore the relationship between cutaneous pain thresholds, Zung Self- Rating Depression Scale (ZUNG-D) scores, Leeds Dependence Questionnaire (LDQ) scores and serum levels of apolipoprotein A1 (APOA1) and apolipoprotein E (APOE) in patients with MOH. Methods 69 patients with MOH and 42 healthy volunteers as control group were enrolled in the study between September 2016 and January 2018. To investigate skin sensitivity, Von Frey-like filaments were applied sequentially to the skin territories innervated by the divisions of the trigeminal nerve, to determine cutaneous pain thresholds. APOA1 and APOE, previously identified as potential biomarkers candidates for the pathophysiology of chronic pain, were quantified in the serum by Enzyme-linked Immunosorbent Assay (ELISA). Results Cutaneous pain thresholds were lower among patients with MOH than healthy controls. Serum APOE was significantly lower in patients with MOH, compared to healthy volunteers (p < 0.01), but no differences were found concerning serum APOA1 (Fig. 1). In patients with MOH, serum APOE was positively related to Body Mass Index, albumin and uric acid, whereas serum APOA1 was positively related to creatinine. Serum APOA1 and APOE did not have any relationship with cutaneous pain thresholds, ZUNG-D scores, LDQ scores and other clinical or laboratory parameters. Conclusions Serum APOE is significantly altered in patients with MOH compared to controls, but it is apparently not correlable with any aspect of the disease. APOE may play a role in the pathophysiology of MOH and the consequences associated with medication overuse; further studies are needed to deepen this finding. Ethics approval This study was performed following the Helsinki Declaration principles and approved by the local Ethical Committee (prot. 2073).

2018 - Urinary proteomics in biomarker discovery of kidney-related disorders: Diabetic nephropathy and drug-induced nephrotoxicity in chronic headache [Articolo su rivista]
Bellei, Elisa; Monari, Emanuela; Bergamini, Stefania; Pini, Luigi Alberto; Tomasi, Aldo; Ozben, Tomris
abstract

Objective Urinary proteomics is primarily applied to the study of renal and urogenital tract disorders. Here are reported two distinct successful examples of this approach for the discovery of early urinary biomarkers of kidney-related dysfunctions: diabetic nephropathy (DN), a well-known complication of diabetes frequently leading to dialysis, and drug-induced nephrotoxicity, a possible condition caused by medication-overuse headache (MOH). Early detection of kidney disorders based on selective biomarkers could permit to diagnose patients at the initial stage of the disease, where the therapy may be suspended or prevent disease advancement. Methods Urine samples were first concentrated and desalted. Subsequently, they were subjected to two-dimensional gel electrophoresis (2-DE) coupled to mass spectrometry (MS) for protein identification. Furthermore, some proteins were verified by Western blot and ELISA test. Results In diabetes-related study, 11 differentially expressed proteins were detected (8 up-regulated and 3 down-regulated) in type 2 diabetic (T2D) and T2DN patients compared to the healthy control subjects. In the MOH study, a total of 21 over-excreted proteins were revealed in urine of non-steroidal anti-inflammatory drugs (NSAIDs) and mixtures abusers vs controls. Particularly, 4 proteins were positively validated by immunoblotting and ELISA. Conclusion Urinary proteomics allows non-invasive assessment of renal diseases at an early stage by the identification of characteristic protein pattern.

2017 - Serum protein changes in a rat model of chronic pain show a correlation between animal and humans [Articolo su rivista]
Bellei, Elisa; Vilella, Antonietta; Monari, Emanuela; Bergamini, Stefania; Tomasi, Aldo; Cuoghi, Aurora; Guerzoni, Simona; Manca, Letizia; Zoli, Michele; Pini, Luigi Alberto
abstract

In previous works we showed the overexpression of some proteins in biological fluids from patients suffering chronic pain. In this proteomic study we analysed serum from a rat model of neuropathic pain obtained by the chronic constriction injury (CCI) of sciatic nerve, at two time intervals, 2 and 5 weeks after the insult, to find proteins involved in the expression or mediation of pain. Sham-operated and CCI rats were treated with saline or indomethacin. Two weeks after ligation, we identified three serum proteins overexpressed in CCI rats, two of which, alpha-1-macroglobulin and vitamin D-binding protein (VDBP), remained increased 5 weeks post-surgery; at this time interval, we found increased levels of further proteins, namely apolipoprotein A-I (APOA1), apolipoprotein E (APOE), prostaglandin-H2 D-isomerase (PTGDS) and transthyretin (TTR), that overlap the overexpressed proteins found in humans. Indomethacin treatment reversed the effects of ligation. The qPCR analysis showed that transcript levels of APOA1, APOE, PTGDS and VDBP were overexpressed in the lumbar spinal cord (origin of sciatic nerve), but not in the striatum (an unrelated brain region), of CCI rats treated with saline 5 weeks after surgery, demonstrating that the lumbar spinal cord is a possible source of these proteins.

2016 - A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants [Articolo su rivista]
Bacchelli, Elena; Cainazzo, Maria Michela; Cameli, Cinzia; Guerzoni, Simona; Martinelli, Angela; Zoli, Michele; Maestrini, Elena; Pini, Luigi Alberto
abstract

Background: Cluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology. Complex genetic factors are likely to play a role in CH etiology; however, no confirmed gene associations have been identified. The aim of this study is to identify genetic variants influencing risk to CH and to explore the potential pathogenic mechanisms. Methods: We have performed a genome-wide association study (GWAS) in a clinically well-defined cohort of 99 Italian patients with CH and in a control sample of 360 age-matched sigarette smoking healthy individuals, using the Infinium PsychArray (Illumina), which combines common highly-informative genome-wide tag SNPs and exonic SNPs. Genotype data were used to carry out a genome-wide single marker case-control association analysis using common SNPs, and a gene-based association analysis focussing on rare protein altering variants in 745 candidate genes with a putative role in CH. Results: Although no single variant showed statistically significant association at the genome-wide threshold, we identified an interesting suggestive association (P = 9.1 × 10−6) with a common variant of the PACAP receptor gene (ADCYAP1R1). Furthermore, gene-based analysis provided significant evidence of association (P = 2.5 × 10−5) for a rare potentially damaging missense variant in the MME gene, encoding for the membrane metallo-endopeptidase neprilysin. Conclusions: Our study represents the first genome-wide association study of common SNPs and rare exonic variants influencing risk for CH. The most interesting results implicate ADCYAP1R1 and MME gene variants in CH susceptibility and point to a role for genes involved in pain processing. These findings provide new insights into the pathogenesis of CH that need further investigation and replication in larger CH samples.

2015 - Nimodipine in otolaryngology: from past evidence to clinical perspectives [Articolo su rivista]
Monzani, Daniele; Genovese, Elisabetta; Pini, Luigi Alberto; DI Berardino, F; Alicandri Ciufelli, Matteo; Galeazzi, Gian Maria; Presutti, Livio
abstract

As L-type voltage-gated calcium channels (VGCCs) control Ca(2+) influx and depolarisation of cardiac and vascular smooth muscle, they represent a specific therapeutic target for calcium channel blockers (CCBs), which are approved and widely used to treat hypertension, myocardial ischaemia and arrhythmias. L-type currents also play a role in calcium entry in the sensory cells of the inner ear. In hair cells of both cochlea and labyrinth, calcium cytoplasmic influx is the first physiological process that activates complex intracellular enzymatic reactions resulting in neurotransmitter release. Excessive calcium ion entry into sensory cells, as a consequence of L-VGCCs malfunction is responsible for over-activation of phospholipase A2 and C, protein kinase II and C, nitric oxide synthase and both endonucleases and depolymerases, which can cause membrane damage and cellular death if the cytoplasmic buffering capacity is overcome. Nimodipine, a highly lipophilic 1-4 dihydropyridine that easily crosses the brain-blood barrier, is generally used to reduce the severity of neurological deficits resulting from vasospasm in patients with subarachnoid haemorrhage. Moreover, due to its selective blocking activity on L-channel calcium currents, nimodipine is also suggested to be an effective countermeasure for cochlear and vestibular dysfunctions known as channelopathies. Indeed, experimental data in amphibians and mammalians indicate that nimodipine has a stronger efficacy than other CCBs (aminopyridine, nifedipine) on voltage-dependent whole-cell currents within hair cells at rest and it is the only agent that is also effective during their mechanically induced depolarisation. In humans, the efficacy of nimodipine is documented in the medical management of peripheral vestibular vertigo, sensorineural hearing loss and tinnitus, even in a pathology as complex as Ménière's disease. Nimodipine is also considered useful in the prophylaxis of damage to the facial and cochlear nerves caused by ablative surgery of cerebellopontine tumours; it has been recently hypothesised to accelerate functional recovery of recurrent nerve lesions during thyroid cancer surgery. Further trials with adequate study design are needed to test the efficacy of nimodipine in the treatment of vertigo due to cerebrovascular disease and vestibular migraine.

2015 - O015. Evaluation of the genetic polymorphism of the α3 (CHRNA3) and α5 (CHRNA5) nicotinic receptor subunits, in patients with cluster headache [Articolo su rivista]
Cainazzo, Maria Michela; Tiraferri, Ilaria; Ciccarese, Michela; Martinelli, Angela; Cameli, Cinzia; Bacchelli, Elena; Zoli, Michele; Pini, Luigi Alberto
abstract

N/A

2015 - Proteomic research of proteins involved in pain expression in an animal model of chronic pain [Articolo su rivista]
Bellei, Elisa; Bergamini, Stefania; Monari, Emanuela; Cuoghi, Aurora; Zoli, Michele; Tomasi, Aldo; Cainazzo, Maria Michela; Guerzoni, Simona; Pini, Luigi Alberto
abstract

nd

2015 - Validation of potential candidate biomarkers of drug-induced nephrotoxicity and allodynia in medication-overuse headache [Articolo su rivista]
Bellei, Elisa; Monari, Emanuela; Bergamini, Stefania; Cuoghi, Aurora; Tomasi, Aldo; Guerzoni, Simona; Ciccarese, Michela; Pini, Luigi Alberto
abstract

Medication-overuse headache (MOH) is a chronic disorder that results from the overuse of analgesics drugs, triptans or other acute headache compounds. Although the exact mechanisms underlying MOH remain still unknown, several studies suggest that it may be associated with development of "central sensitization", which may cause cutaneous allodynia (CA). Furthermore, the epidemiology of drug-induced disorders suggests that medication overuse could lead to nephrotoxicity. The aim of this work was to confirm and validate the results obtained from previous proteomics studies, in which we analyzed the urinary proteome of MOH patients in comparison with healthy non-abusers individuals.

2014 - Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial [Articolo su rivista]
Sarchielli, Paola; Messina, Paolo; Cupini, Letizia M; Tedeschi, Gioacchino; Di Piero, Vittorio; Livrea, Paolo; Pini, Luigi Alberto; Bernardi, Giorgio; Bono, Giorgio; Sandrini, Giorgio; Caproni, Stefano; Corbelli, Ilenia; Pisani, Francesco; Beghi, Ettore; Calabresi, Paolo
abstract

To assess the efficacy, safety and tolerability of sodium valproate (800mg/die) compared with placebo in medication-overuse headache patients with a history of migraine without aura.

2013 - A preliminary study on the relationship between central auditory processing and childhood primary headaches in the intercritical phase [Articolo su rivista]
Ciriaco, Antonella; Russo, Angelo; Monzani, Daniele; Genovese, Elisabetta; Benincasa, Paola; Caffo, Ernesto; Pini, Luigi Alberto
abstract

Recently, an increasing number of articles have appeared on central auditory processing disorders, but in the literature there is only one study that evaluated the possible correlation between migraine in the critical phase and central auditory processing. The aim of our study was to assess the correlation between auditory processing information and childhood primary headaches in the intercritical phase.

2013 - An unusual case report on the possible role of Warfarin in migraine prophylaxis [Articolo su rivista]
Russo, Angelo; Santi, Sara; Gueraldi, Daniela; De Paola, Maria; Zani, Fabiana; Pini, Luigi Alberto
abstract

Migraine is a complex disease whose physiopathological mechanisms are still not completely revealed.

2013 - Chronic headache and medication overuse: analysis of patients and medical interventions [Abstract in Rivista]
Ferrari, Anna; E., Sternieri; M. M., Cainazzo; S., Guerzoni; F., Gori; I., Tiraferri; M., Ciccarese; Pini, Luigi Alberto
abstract

Introduction: The lack of standardized approaches makes it more difficult than is the case for episodic headaches the evaluation of the outcomes of the process of care to patients with chronic headache and medication overuse. The aim of this study was to analyse, critically, both the characteristics of chronic headache patients and the way they are managed. Methods: We reviewed all the medical records of patients admitted to the Day Hospital of the Headache Centre in the second semester of 2012. Results: Eighty female patients (mean age 52 years) had been admitted to the Day Hospital; 42% of them had already been hospitalized at least once, even in the 3 previous years. The headache had started as episodic with menarche in 38% of patients and it had become chronic on average after 22 years. All patiens made overuse of prescription medications: 70% NSDAIDs; 49% triptans; 19% combination of indomethacin, prochlorperazine and caffeine; 7.5% combination of codeine and paracetamol; 6.3% combination of butalbital, propyphenazone and caffeine; 6.3% tramadol. Fifty-two percent of the patients had previously taken at least three prophylactic treatments. During the hospitalization several lab tests and consultations had been carried out. Discussion: Medication-overuse no longer appears as a consequence of the barriers that the headache patients, particularly migraine sufferers, encounter to access to health care. In fact, most of the patients examined were taking prescription medications, prophylactic treatments and were regularly followed by the Centre and by other specialists for years. Conclusion: Patients with chronic headache and medication overuse are now intensely medicalized without decisive benefits and with the risk that their condition being crystallized even more as chronic and intractable. This categorization could impede the research of different and more effective interventions by physicians and patients.

2013 - Discovery by a proteomic approach of possible early biomarkers of drug-induced nephrotoxicity in medication-overuse headache [Articolo su rivista]
Bellei, Elisa; Monari, Emanuela; Cuoghi, Aurora; Bergamini, Stefania; Guerzoni, Simona; Ciccarese, Michela; Ozben, T.; Tomasi, Aldo; Pini, Luigi Alberto
abstract

BACKGROUND: Medication-overuse headache (MOH) is a chronic headache condition that results from the overuse of analgesics drugs, triptans, or other antimigraine compounds. The epidemiology of drug-induced disorders suggests that medication overuse could lead to nephrotoxicity, particularly in chronic patients. The aim of this work was to confirm and extend the results obtained from a previous study, in which we analyzed the urinary proteome of 3 MOH patients groups: non-steroidal anti-inflammatory drugs (NSAIDs), triptans and mixtures abusers, in comparison with non-abusers individuals (controls). METHODS: In the present work we employed specialized proteomic techniques, namely two-dimensional gel electrophoresis (2-DE) coupled with mass spectrometry (MS), and the innovative Surface-Enhanced Laser Desorption/Ionization Time-of-Flight mass spectrometry (SELDI-TOF-MS), to discover characteristic proteomic profiles associated with MOH condition. RESULTS: By 2-DE and MS analysis we identified 21 over-excreted proteins in MOH patients, particularly in NSAIDs abusers, and the majority of these proteins were involved in a variety of renal impairments, as resulted from a literature search. Urine protein profiles generated by SELDI-TOF-MS analysis showed different spectra among groups. Moreover, significantly higher number of total protein spots and protein peaks were detected in NSAIDs and mixtures abusers. CONCLUSIONS: These findings confirm the presence of alterations in proteins excretion in MOH patients. Analysis of urinary proteins by powerful proteomic technologies could lead to the discovery of early candidate biomarkers, that might allow to identify MOH patients prone to develop potential drug overuse-induced nephrotoxicity.

2013 - Impact of continuing or quitting smoking on episodic cluster headache: a pilot survey [Articolo su rivista]
Ferrari, Anna; Maurizio, Zappaterra; Federica, Righi; Michela, Ciccarese; Ilaria, Tiraferri; Pini, Luigi Alberto; Simona, Guerzoni; Maria, Cainazzo
abstract

Abstract BACKGROUND: The majority of patients suffering from cluster headache (CH) are smokers and it has been suggested that smoking may trigger the development of CH. The aim of this pilot survey was to describe: 1. the differences between current, former, and never smokers CH patients; 2. if smoking changed during an active cluster period; 3. if CH changed after quitting. METHODS: All outpatients with episodic CH according to the criteria of ICHD-II who were consecutively seen for the first time from October 2010 to April 2012 at a headache centre were interviewed by phone using a specifically prepared questionnaire. Statistical differences between continuous variables were analysed by the Student's t-test or the one-way analysis of variance (ANOVA), followed by Newman-Keuls post-hoc testing. Comparisons between percentages were made using the Chi-square test or Fisher's exact test. All data were expressed as the mean ± standard deviation (SD). RESULTS: Among a total of 200 patients surveyed (172 males, 28 females; mean age ± SD: 48.41 ± 12 years) there were 60%, 21%, and 19% of current, former, and never smokers, respectively. Current smokers reported longer active periods (12.38 ± 10 weeks) and a higher maximum number of attacks per day (3.38 ± 1) compared to never smoker CH patients (5.68 ± 4 weeks, P &lt;0.05 and 2.47 ± 1, P &lt;0.05, respectively). During the active period most of the patients stated to decrease (45.7%) or not to change (45.7%) the number of cigarettes smoked. Among those who decreased smoking, most (83.8%) reported that they had less desire to smoke. After quitting, the majority of former smokers stated that their headache had not changed. CONCLUSIONS: Patients with episodic CH who are also smokers appear to have a more severe form of the disorder. However, it is unlikely that between CH and smoking there is a causal relationship, as CH patients rarely improve quitting smoking.

2013 - The omics in migraine [Articolo su rivista]
Lionetto, Luana; Gentile, Giovanna; Bellei, Elisa; Capi, Matilde; Sabato, Donata; Marsibilio, Francesco; Simmaco, Maurizio; Pini, Luigi Alberto; Martelletti, Paolo
abstract

The term omics consist of three main areas of molecular biology, such as genomics, proteomics and metabolomics. The omics synergism recognise migraine as an ideal study model, due to its multifactorial nature. In this review, the plainly research data featuring in this complex network are reported and analyzed, as single or multiple factor in pathophysiology of migraine. The future of migraine biomolecular research shall be focused on networking among these different and hierarchical disciplines. We have to look for its Ariadne's tread, in order to see the whole painting of migraine molecular biology.

2012 - A CB1 agonist in the treatment of medication-overuse headache: a possible therapeutic strategy [Abstract in Rivista]
S., Guerzoni; M., Ciccarese; M., Zappaterra; Pini, Luigi Alberto
abstract

To evaluate efficacy and safety of CB1 agonist (nabilone) in reducing pain and frequency of headache, the number of analgesic intake and in increasing the quality of life of patients with long-standing intractable MOH. Nabilone, a cannabinoid 1-receptor agonist would appear beneficial for patients suffering from MOH, primarily in reducing the intensity of pain and analgesic intake. Side effects were infrequent, of mild intensity and disappeared after discontinuation of the treatment. This is the first randomised, controlled, trial in which nabilone appeared to be safe, although larger-scale studies are required to confirm and identify the optimum treatment for these patients with intractable headache.

2012 - CHRNA5 polymorphism and nicotine dependence in patients with cluster headache [Abstract in Rivista]
I., Tiraferri; M., Ciccarese; M. M., Cainazzo; Ferrari, Anna; Zoli, Michele; Pini, Luigi Alberto
abstract

Up to 90% of cluster headache (CH) patients have a prolonged history of cigarette smoking prior to the headache onset. A genetic link has been suggested between CH and nicotine addiction and, also, that agents found in cigarette smoke have a direct effect on the hypothalamus, a pivotal area for the pathogenesis of CH . Case-control and genome-wide association studies have reported links between single nucleotide polymorphisms (SNPs) in the alpha-5 nicotinic acetylcholine receptor subunit (CHRNA5) genes and cigarettes smoked per day (CPD). In particular, in vivo studies have demonstrated that 5 subunit is involved in controlling nicotine intake, in mediating nicotine withdrawal symptoms and in affecting anxiety-related behaviour.

2012 - Comparison of tolerability and efficacy of a combination of paracetamol + caffeine and sumatriptan in the treatment of migraine attack: a randomized, double-blind, double-dummy, cross-over study. [Articolo su rivista]
Pini, Luigi Alberto; Guerzoni, S; Cainazzo, M; Ciccarese, M; Prudenzano, Mp; Livrea, P.
abstract

In this study, we compared the efficacy and tolerability of the combination of paracetamol 1,000 mg + caffeine 130 mg (PCF) with sumatriptan 50 mg (SUM) in migraine attacks. This was a multi-center randomized double-blind, double-dummy, cross-over controlled trial. The efficacy was assessed by the sum of pain intensity differences, the curve of mean pain intensity, the number of pain free at 2 h, and the total pain relief. Tolerability was assessed by recording adverse events within 4 h after drug assumption and evaluating the global judgement of patients. The comparison of these parameters did not show differences between the two drugs which resulted absolutely overlapping in pain relief and patients evaluation. In conclusion, we confirm the efficacy and safety of PCF such as SUM in the treatment of migraine attacks.

2012 - Efficacy of frovatriptan versus almotriptan for acute treatment of menstrual migraine: analysis of a double-blind, randomized, crossover, multicentre Italian, comparative study [Abstract in Rivista]
M., Bartolini; M. A., Giamberardino; C., Lisotto; P., Martelletti; D., Moscato; B., Panascia; L., Savi; Pini, Luigi Alberto; G., Sances; P., Santoro; G., Zanchin; S., Omboni; M. D., Ferrari; B., Fierro; F., Brighina
abstract

To compare the efficacy and safety of frovatriptan and almotriptan in women with menstrually related migraine (ICHD-II criteria) enrolled in a multicentre, randomized, double-blind, crossover study. Conclusions Frovatriptan was as effective as almotriptan in the immediate treatment of menstrually related migraine attacks. However, it showed a more favorable sustained effect, as shown by a lower rate of migraine recurrence.

2012 - Evaluation of a possible relationship between medication-overuse headache and potential renal dysfunctions by a proteomic study on urine samples [Abstract in Rivista]
Bellei, Elisa; Monari, Emanuela; Bergamini, Stefania; Cuoghi, Aurora; Tomasi, Aldo; Guerzoni, Simona; A., Bazzocchi; Pini, Luigi Alberto
abstract

This proteomic study confirms the previous finding of alterations in urinary proteins excreted in MOH patients. Some of these proteins, identified as over-expressed particularly in NSAIDs abusers, were related to different renal dysfunctions and, probably in the development of CA. Proteomic analysis of urine proteins by the combination of 2-DE and MS could improve the knowledge of the pathophysiology of the MOH condition and identify early biomarkers to prevent the potential drug overuse-induced nephrotoxicity

2012 - Frovatriptan versus almotriptan for acute treatment of menstrual migraine: analysis of a double-blind, randomized, cross-over, multicenter, Italian, comparative study [Articolo su rivista]
Bartolini, Marco; Giamberardino, Maria Adelaide; Lisotto, Carlo; Martelletti, Paolo; Moscato, Davide; Panascia, Biagio; Savi, Lidia; Pini, Luigi Alberto; Sances, Grazia; Santoro, Patrizia; Zanchin, Giorgio; Omboni, Stefano; Ferrari, Michel D; Fierro, Brigida; Brighina, Filippo
abstract

The objective of the study was to compare the efficacy and safety of frovatriptan and almotriptan in women with menstrually related migraine (IHS Classification of Headache disorders) enrolled in a multicenter, randomized, double-blind, cross-over study. Patients received frovatriptan 2.5 mg or almotriptan 12.5 mg in a randomized sequence: after treating 3 episodes of migraine in no more than 3 months with the first treatment, the patient was switched to the other treatment. 67 of the 96 female patients of the intention-to-treat population of the main study had regular menstrual cycles and were thus included in this subgroup analysis. 77 migraine attacks classified as related to menses were treated with frovatriptan and 78 with almotriptan. Rate of pain relief at 2 and 4 h was 36 and 53 % for frovatriptan and 41 and 50 % for almotriptan (p = NS between treatments). Rate of pain free at 2 and 4 h was 19 and 47 % with frovatriptan and 29 and 54 % for almotriptan (p = NS). At 24 h, 62 % of frovatriptan-treated and 67 % of almotriptan-treated patients had pain relief, while 60 versus 67 % were pain free (p = NS). Recurrence at 24 h was significantly (p < 0.05) lower with frovatriptan (8 vs. 21 % almotriptan). This was the case also at 48 h (9 vs. 24 %, p < 0.05). Frovatriptan was as effective as almotriptan in the immediate treatment of menstrually related migraine attacks. However, it showed a more favorable sustained effect, as shown by a lower rate of migraine recurrence.

2012 - Italian guidelines for primary headaches: 2012 revised version. [Articolo su rivista]
Sarchielli, P; Granella, F; Prudenzano, Mp; Pini, Luigi Alberto; Guidetti, V; Bono, G; Pinessi, L; Alessandri, M; Antonaci, F; Fanciullacci, M; Ferrari, Anna; Guazzelli, M; Nappi, G; Sances, G; Sandrini, G; Savi, L; Tassorelli, C; Zanchin, G.
abstract

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105-190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version.

2012 - Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. [Articolo su rivista]
Pini, Luigi Alberto; S., Guerzoni; M. M., Cainazzo; Ferrari, Anna; P., Sarchielli; I., Tiraferri; M., Ciccarese; M., Zappaterra
abstract

Medication overuse headache (MOH) is a severe burden to sufferers and its treatment has few evidence-based indications. The aim of this study is to evaluate efficacy and safety of nabilone in reducing pain and frequency of headache, the number of analgesic intake and in increasing the quality of life on patients with long-standing intractable MOH. Thirty MOH patients were enrolled at the University of Modena's Interdepartmental Centre for Research on Headache and Drug Abuse (Italy) in a randomized, double-blind, active-controlled, crossover study comparing nabilone 0.5 mg/day and ibuprofen 400 mg. The patients received each treatment orally for 8 weeks (before nabilone and then ibuprofen or vice versa), with 1 week wash-out between them. Randomization and allocation (ratio 1:1) were carried out by an independent pharmacy through a central computer system. Participants, care givers, and those assessing the outcomes were blinded to treatment sequence. Twenty-six subjects completed the study. Improvements from baseline were observed with both treatments. However, nabilone was more effective than ibuprofen in reducing pain intensity and daily analgesic intake (p &lt; 0.05); moreover, nabilone was the only drug able to reduce the level of medication dependence (-41 %, p &lt; 0.01) and to improve the quality of life (p &lt; 0.05). Side effects were uncommon, mild and disappeared when nabilone was discontinued. This is the first randomized controlled trial demonstrating the benefits of nabilone on headache, analgesic consumption and the quality of life in patients with intractable MOH. This drug also appears to be safe and well-tolerated. Larger scale studies are needed to confirm these preliminary findings

2012 - Proteomic analysis of urine in medication-overuse headache patients: possible relation with renal damages [Articolo su rivista]
Bellei, Elisa; Cuoghi, Aurora; Monari, Emanuela; Bergamini, Stefania; Fantoni, Luca Isaia; Zappaterra, Maurizio; Guerzoni, Simona; Bazzocchi, Annalisa; Tomasi, Aldo; Pini, Luigi Alberto
abstract

Medication-overuse headache (MOH) is a chronic disorder associated with overuse of analgesic drugs, triptans, non-steroidal anti-inflammatory drugs (NSAIDs) or other acute headache compounds. Various epidemiologic investigations proved that different drug types could cause nephrotoxicity, particularly in chronic patients. The aim of the present work was to analyze, by aproteomic approach, the urinary protein profiles of MOH patients focusing on daily use of NSAIDs, mixtures and triptans that could reasonably be related to potential renal damage. We selected 43 MOH patients overusing triptans (n = 18), NSAIDs (n = 11), and mixtures (n = 14), for 2–30 years with a mean daily analgesic intake of 1.5 ± 0.9 doses, and a control group composed of 16 healthy volunteers. Urine proteins were analyzed by monodimensional gel electrophoresis and identified by mass spectrometry analysis. Comparing the proteomic profiles of patients and controls, we found a significantly different protein expression, especially in the NSAIDs group, in which seven proteins resulted over-secreted from kidney (OR = 49, 95% CI 2.53–948.67 vs. controls; OR = 11.6, 95% CI 0.92–147.57 vs. triptans and mixtures groups). Six of these proteins (uromodulin, a-1-microglobulin, zinc-a-2- glycoprotein, cystatin C, Ig-kappa-chain, and inter-a-trypsin heavy chain H4) were strongly correlated with various forms of kidney disorders. Otherwise, in mixtures and in triptans abusers, only three proteins were potentially associated to pathological conditions (OR = 4.2, 95% CI 0.33–53.12, vs. controls). In conclusion, this preliminary proteomic study allowed us to define the urinary protein pattern of MOH patients that is related to the abused drug. According with the obtained results, we believe that the risk of nephrotoxicity should be considered particularly in MOH patients who abuse of NSAIDs.

2012 - Relationship between childhood physical maltreatment and migraine: a case report [Abstract in Rivista]
A., Russo; S., Santi; Pini, Luigi Alberto
abstract

Primary headaches are multifactorial syndromes whose therapy involves different branches of medicine, also including psychological, social and economic aspects, thus making therapeutic approach by one specific discipline impossible. The role of psychological factors in the pathogenesis, course and treatment of primary headache is a major topic both for researchers and clinicians. The increasing attention of the scientific community towards psychiatric comorbidity in patients with migraine, has produced a significant amount of publications in all major journals. Several studies showed that abuse could be the cause of the onset of migraine, as well as, the indicator of a worse prognosis.

2012 - The relationship between social support, and couple’s relationship in chronic headache [Abstract in Rivista]
M., De Paola; F., Zani; P., Vandelli; C., Raimondi; Ferrari, Anna; Pini, Luigi Alberto; M. M., Cainazzo
abstract

Health psychology investigates the role of the family and social support as a key factor for mediating stress in situations of chronic illness. As regards to chronic headache, there are few studies that correlate this condition with the perception of social support in patients. In fact, patients with chronic headache use little social support as a coping strategy, despite this, it is considered an important strategy in the management of disease. It has been reported that poor social support perceived by patients with chronic headache is related to a perception of high stress levels; the patients with chronic headaches, also, could have more difficulties in maintaining social relationships. The family support is more important than social support for MOH patients.

2012 - The use of migraine preventative drugs on current clinical practice. An analysis based on a series of 400 patients [Abstract in Rivista]
M., Bellamio; M., Margoni; Pini, Luigi Alberto; C., Lisotto; C., Disco; F., Maggioni; G., Zanchin
abstract

In 2002 the Italian Society for the Study of Headaches (SISC) introduced a second version of guidelines (GL) aimed to determine the most appropriate choice of drugs for the therapy of migraine. The impact of preventative GL in the general practice had been assessed in 1999, when drug use was evaluated respectively before (1989-92, n 351) and after (1995-98, n 204) the introduction of 1993 GL. Our aim was to establish the impact in migraine patients using the 2002 SISC GL. The common use of migraine preventative drugs in current clinical practice differs in many aspects from the 2002 SISC GL. Very relevant is the fact that the number of patients who, despite having the indication for preventative treatment are not receiving it, is very high (58.3%) and remains substantially unchanged during the years. A more adequate diffusion of the just published 2011 GL should be planned in order to effectively impact current practice. Furthermore, the promotion of the use of a headache diary could improve the therapeutic choice when a preventative strategy is being considered.

2011 - A double-blind, randomized, multicenter, Italian study of frovatriptan versus almotriptan for the acute treatment of migraine. [Articolo su rivista]
Bartolini, M.; Giamberardino, M. A.; Lisotto, C.; Martelleltti, P.; Moscato, D.; Panascia, B.; Savi, L.; Pini, Luigi Alberto; Sances, G.; Santoro, P.; Zanchin, G.; Omboni, S.; Ferrari, M. D.; Brighina, F.; Fierro, B.
abstract

The objective of this study was to evaluate patients' satisfaction with acute treatment of migraine with frovatriptan or almotriptan by preference questionnaire. One hundred and thirty three subjects with a history of migraine with or without aura (IHS 2004 criteria), with at least one migraine attack in the preceding 6 months, were enrolled and randomized to frovatriptan 2.5 mg or almotriptan 12.5 mg, treating 1-3 attacks. The study had a multicenter, randomized, double blind, cross-over design, with treatment periods lasting <3 months. At study end patients assigned preference to one of the treatments using a questionnaire with a score from 0 to 5 (primary endpoint). Secondary endpoints were pain free and pain relief episodes at 2 and 4 h, and recurrent and sustained pain free episodes within 48 h. Of the 133 patients (86%, intention-to-treat population) 114 of them expressed a preference for a triptan. The average preference score was not significantly different between frovatriptan (3.1 ± 1.3) and almotriptan (3.4 ± 1.3). The rates of pain free (30% frovatriptan vs. 32% almotriptan) and pain relief (54% vs. 56%) episodes at 2 h did not significantly differ between treatments. This was the case also at 4 h (pain free: 56% vs. 59%; pain relief: 75% vs. 72%). Recurrent episodes were significantly (P < 0.05) less frequent under frovatriptan (30% vs. 44%), also for the attacks treated within 30 min. No significant differences were observed in sustained pain free episodes (21% vs. 18%). The tolerability profile was similar between the two drugs. In conclusion, our study suggests that frovatriptan has a similar efficacy of almotriptan in the short-term, while some advantages are observed during long-term treatment

2011 - An emerging problem in clinical practice: how to treat chronic headache patients. [Articolo su rivista]
Pini, Luigi Alberto
abstract

not available

2011 - Analysis on the use of migraine preventative drugs in current clinical practice [Abstract in Rivista]
Bellamio, M.; Margoni, M.; Disco, C.; Pini, Luigi Alberto; Maggioni, F.; Zanchin, G.
abstract

NA

2011 - Basal cutaneous pain threshold in headache patients [Articolo su rivista]
Zappaterra, M.; Guerzoni, S.; Cainazzo, M. M.; Ferrari, Anna; Pini, Luigi Alberto
abstract

The aim of this study was to analyze cutaneous pain threshold (CPT) during the interictal phase in headache patients, and the relationships between headache frequency and analgesic use. A consecutive series of 98 headache patients and 26 sex- and age-balanced controls were evaluated. Acute allodynia (AA) was assessed by Jakubowski questionnaire, and interictal allodynia (IA) by a skin test with calibrated monofilaments. AA is widely known as a symptom more present in migraine than in TTH spectrum: in our study this was confirmed only in cases of episodic attacks. When headache index rises towards chronicization, the prevalence of AA increases in both headache spectrums (χ (2) 13.55; p &lt; 0.01). AA was associated with IA only in cases of chronic headache. When headache becomes chronic, mostly in presence of medication overuse, interictal CPT decreases and IA prevalence increases (χ (2) 20.44; p &lt; 0.01), with closer association than AA. In MOH patients there were no significant differences depending on the diagnosis of starting headache (migraine or tension type headache) and, in both groups, we found the overuse of analgesics plays an important role: intake of more than one daily drug dramatically reduces the CPT (p &lt; 0.05). Thus, when acute allodynia increases frequency, worsens or appears for the first time in patients with a long-standing history of chronic headache, it could reasonably suggest that the reduction of CPT had started, without using a specific practical skin test but simply by questioning clinical headache history. In conclusion, these results indicate that the role of medication overuse is more important than chronicization in lowering CPT, and suggest that prolonged periods of medication overuse can interfere with pain perception by a reduction of the pain threshold that facilitates the onset of every new attack leading to chronicization.

2011 - Cigarette smoking may sustain the active phase of episodic cluster headache [Abstract in Rivista]
Cainazzo, M. M.; Righi, Federica; Tiraferri, Ilaria; Zappaterra, Maurizio; Ciccarese, Michela; Trianni, G. L.; Pini, Luigi Alberto; Ferrari, Anna
abstract

The aim of our study was to explore the relationship between cigarette smoking and the course cluster headache. The preliminary results suggest that cigarette smoking is an aggravating factor for cluster headache.

2011 - Evaluation of the analgesic effect of nabilone versus acetaminophen plus caffeine in an inflammatory pain model (tail flik test) in rats. [Abstract in Rivista]
Ciccarese, M; Ruggeri, V; Cainazzo M., M; Ferrari, Anna; Pini, Luigi Alberto
abstract

Nabilone is a synthetic cannabinoid with a potent agonist effect on CB1 cannabinoid receptors, involved in the regulation of nausea, vomiting, appetite, movement and pain. Several clinical trials confirm the effectiveness of nabilone in treating anxiety and pain associated with fibromyalgia or multiple sclerosis. Nabilone, in man, shows its analgesic/anti-inflammatory activity, and its modulation of allodynia without having significant psychotropic effects. Modification of endogenous cannabinoid (anandamide) has been found in animal model of pain, inflammation and neurological disease. Anandamide and cannabidiol are weak agonists of TPRV1 receptors, normally activated by noxious physical/thermal stimuli or by inflammatory hyperalgesia. The aim of our study was to evaluate the effect of Nabilone and combination of acetaminophen plus caffeine in acute and chronic treatment on hyperalgesia induced by nitro-glycerine (NTG), using tail flick test, in rats. We choose nitro-glycerine as nitric oxide (NO) donor; infusion of NO induces delayed headache in migraineurs and activity of neurons in the spinal trigeminal nucleus. Method 12 Adult male Wistar rats (weight range: 180-355 g) were treated, in acute, with nabilone (2,5 mg/kg p.o.), acetaminophen plus caffeine (400 mg/Kg p.o. + 52 mg/Kg p.o.); and, in chronic (8 days) with nabilone (1 mg/Kg p.o.), acetaminophen plus caffeine (200 mg/Kg p.o.+ 26 mg/Kg p.o.), or vehicle, 1 h before the i.p. injection of NTG (10 mg/kg) (18-20 degrees C). Tail flick test was performed during acute treatment, 2-4 hours after injection of NTG; during chronic treatment after a period of 8 days. The test has been conducted with a tail flick device that use a 375-W movie light focused on the rat’s tail (2-3 cm from the tip) by means of a condenser lens positioned below the light source. The latency time (sec) was evaluated as the time between the beginning of test and the deviation of tail. The highest execution time to avoid tissue damage was 15 sec. Results The treatment with nabilone increased the latency time, during tail flick test vs. controls; in fact the latency time was 15 ± 0.8 sec. (mean ± SD) and 10 ± 0.5 sec. (mean ± SD), respectively in acute and in chronic treatment; rats treated with acetaminophen, 400 or 200 mg/Kg p.o. plus caffeine 52 or 26 mg/kg p.o., respectively, in acute and in chronic administration did not show changes vs. controls (2,7 ± 0.3 sec.; ANOVA and Bonferroni‘ s test; p< 0.05). Conclusion The data supported the efficacy of nabilone in the management of acute and chronic pain. Our main interest was to explore its potential use in the treatment of chronic headache, providing a novel target for an innovative therapeutic approach. Balapal S et al., (2007) Curr Neuropharmacol 5: 81-97 Dieterle A et al., (2011) Cephalalgia 31: 31-42

2011 - Migraine preventive drug-induced weight gain may be mediated by effects on hypothalamic peptides: the results of a pilot study. [Articolo su rivista]
Caproni, S; Corbelli, I; Pini, Luigi Alberto; Cupini, Ml; Calabresi, P; Sarchielli, P.
abstract

AIMS: This study was aimed to verify changes in the levels of hypothalamic neuropeptides in migraineurs under preventive treatment with amitryptiline and flunarizine. Thirty-nine migraine patients with a body mass index <25 kg/m(2) and without endocrinological or metabolic diseases were assigned to two treatment groups, one receiving amitryptiline, the other flunarizine, for 3 months. Orexin-A, orexin-B and neuropeptide-Y plasma levels were measured at the basal time, at the 1st, 2nd and 3rd months of preventive treatment. RESULTS: A statistically significant reduction in plasma orexin-A and orexin-B levels emerged in both groups. Conversely, plasma neuropeptide-Y levels were markedly increased, with the highest levels at the 2nd and 3rd months, in both patient groups. Orexin-A levels were also negatively correlated to weight gain in both groups during the treatment period. CONCLUSIONS: These results suggest that changes in the levels of hypothalamic orexinergic peptides may contribute to body weight increase occurring in migraineurs during amitryptiline or flunarizine prophylactic treatment.

2011 - Potential toxicity of oxycodone overuse in chronic headaches [Abstract in Rivista]
Guerzoni, S.; Tiraferri, Ilaria; Bazzocchi, Annalisa; Neri, Laura; Pini, Luigi Alberto
abstract

NA

2011 - Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. A comment. [Articolo su rivista]
Mggioni, F.; Pini, Luigi Alberto; Zanchin, G.
abstract

non available

2011 - Psycological profiles in tobacco and drug abusers [Abstract in Rivista]
De Paola, M.; Ferrari, Anna; Raimondi, C.; Neri, Laura; Zappaterra, Maurizio; Vandelli, P.; Pini, Luigi Alberto; Cainazzo, M. M.
abstract

The aim of our study was to evaluate, using specific and validated tests the analogies and differences, with respect to the psychopatological profile between drug abusers and smokers. Our results suggested that the psychological well-being of headache patients who abused of analgesics was more impaired than that of smokers.

2011 - Psycological, audiological and vestibular assesment in primary paediatric headache [Abstract in Rivista]
Ciriaco, Antonella; Caffo, Ernesto; Genovese, Elisabetta; Monzani, Daniele; Benincasa, P.; Pini, Luigi Alberto
abstract

NA

2011 - Rizatriptan efficacy is not related to the occurence of cutaneous allodyniain migrain without aura [Abstract in Rivista]
Granella, F.; Zucco, R.; Ferrari, Anna; Cainazzo, M. M.; Bonazzi, A.; Sternieri, E.; Pini, Luigi Alberto
abstract

Aim of this study was to accertain if the occurrence of cutaneous allodynia was related to the efficacy of triptans in a naturalistic setting. The efficacy of rizatriptan 10 mg wafer at 2 and 24 h seems to be mainly driven by the severity of pain at the moment of drug administration.

2011 - Urine proteomic analysis in patients with cronic headache and overuse of analgesic drugs: possible relation with renal damage [Abstract in Rivista]
Bellei, Elisa; Bergamini, Stefania; Cuoghi, Aurora; Monari, Emanuela; Tomasi, Aldo; Zappaterra, Maurizio; Bazzocchi, Annalisa; Guerzoni, Simona; Pini, Luigi Alberto
abstract

NA

2011 - What Italian say about headache [Abstract in Rivista]
Prudenzano, M. P.; Merico, L.; Livrea, P.; Modica, D.; Lanaia, F.; D'Ippolito, M.; Cupini, L. M.; Buzzi, M. G.; Maggioni, F.; Zanchin, G.; Guaschino, E.; Sances, G.; Corbelli, I.; Sarchielli, P.; Pini, Luigi Alberto
abstract

NA

2010 - Efficacia di rizatriptan in relazione alla presenza di allodinia cutanea in pazienti affetti da emicrania senz’aura. Risultati preliminari. [Poster]
F., Granella; R., Zucco; Ferrari, Anna; Mm, Cainazzo; A., Bonazzi; E., Sternieri; Pini, Luigi Alberto
abstract

Introduzione - L’allodinia cutanea (AC) è caratterizzata dalla percezione di dolore o fastidio provocata da una stimolazione non dolorosa della cute. Burstein per primo [1] ha messo in evidenza la frequente occorrenza di AC durante gli attacchi di emicrania e ne ha correlato la presenza all’inefficacia dei triptani. Gli studi di Burstein sono stati tuttavia condotti su casistiche limitate, mentre clinical trials successivi non hanno confermato la presenza di una correlazione negativa tra efficacia dei triptani e AC. Scopo del presente studio è quello di accertare, in un setting naturalistico (che prevede l’assunzione di un triptano - rizatriptan 10 mg -, a qualsiasi timing e con qualunque severità del dolore durante attacchi di emicrania senz’aura), se la presenza di AC è correlata all’efficacia dei triptani. Metodi – Verranno inclusi nello studio 120 pazienti affetti da emicrania senz’aura (EsA). Vengono qui presentati i risultati preliminari riferiti ai primi 47 pazienti arruolati. Durante la prima visita sono stati consegnati ai pazienti due diari della cefalea per il trattamento di altrettanti attacchi di EsA ed è stato loro raccomandato di assumere rizatriptan wafer 10 mg, nel momento che ritenessero più opportuno. Oltre a variabili concernenti le caratteristiche della cefalea, il timing dell’assunzione di rizatriptan e gli esiti della somministrazione del farmaco a 2 e a 24 ore, il diario conteneva anche un questionario con 8 items sull’AC [2]. L’outcome principale era rappresentato dalla percentuale di pazienti liberi da dolore a 2 ore dall’assunzione del farmaco nei gruppi con (AC+) e senza (AC-) AC. Risultati – Sono entrati nello studio 47 pazienti (F 87%, età media 37,3 anni). L’assunzione di rizatriptan è avvenuta in media 88 minuti dopo l’esordio dell’attacco; l’intensità del dolore era lieve nel 13% dei pazienti e moderata-severa nell’87%. A 2 ore dall’assunzione del farmaco era libero da dolore il 26,5% dei pazienti AC+ vs il 69,2% dei pazienti AC- (p = 0,02); libertà sostenuta dal dolore era presente nel 14,7% dei pazienti AC+ e nel 61,5% dei pazienti AC- (p = 0,003). I pazienti con dolore lieve erano pain-free a 2 ore nel 83,3% dei casi e a 24 ore nel 66,7% dei casi contro il 31,7% (p = 0,02) e il 22,0% (p = 0,04) rispettivamente dei pazienti con dolore moderato-grave. Conclusioni – L’efficacia di rizatriptan sembra inferiore nei pazienti con AC. Rimane da accertare se si tratti di un effetto primitivamente dovuto all’AC oppure secondario alla severità del dolore. Bibliografia [1] Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000;47:614–624 [2] Ashkenazi A, Silberstein S, Jakubowski M, Burstein R. Improved identification of allodynic migraine patients using a questionnaire. Cephalalgia 2007;27:325-329

2010 - Lack of association between five serotonin metabolism-relatedgenes and medication overuse headache. [Articolo su rivista]
S., Cevoli; N., Marzocchi; S., Capellari; C., Scapoli; G., Pierangeli; D., Grimaldi; F., Naldi; Pini, Luigi Alberto; P., Montagna; P., Cortelli
abstract

Serotonin is involved in several central nervous system functions including pain threshold, mood regulation and drug reward. Overuse of acute medications is commonly identified as a causative factor for medication overuse headache (MOH). Apparently, MOH shares with other kinds of drug addiction some common neurobiological pathways. The objective of this study is to assess the role of serotonin metabolism genes in the genetic liability to MOH. We performed a genetic association study using polymorphisms of five serotonin metabolism-related genes: serotonin transporter (5HTT), serotonin receptor 1A(5-HT1A), serotonin receptor 1B (5-HT1B), serotonin receptor 2A (5-HT2A) and serotonin receptor 6 (5HT6)genes. We compared 138 patients with MOH with a control sample of 117 individuals without headache and without drug overuse, and with 101 patients with migraine without aura but without drug overuse (MO). The genotypic and allelic distributions of all polymorphisms investigated didnot differ among the three groups. In conclusion, our studydoes not provide evidence that the 5HTT, 5-HT1A, 5HT1B,5HT2A and 5HT6 gene polymorphisms play a role in the genetic predisposition to MOH.

2010 - The antinociceptive effect of acetylsalicylic acid is differently affected by a CB1 agonist or antagonist and involves the serotonergic system in rats [Articolo su rivista]
Ruggieri, Valentina; Vitale, Giovanni; Filaferro, Monica; Frigeri, Claudio; Pini, Luigi Alberto; Sandrini, Maurizio
abstract

Combinations of non steroidal anti-inflammatory drugs (NSAIDs) and cannabinoids are promising because of their potential synergistic effects in analgesia, resulting in a reduction in dosage and minimizing adverse reactions. The analgesic effect of Acetylsalicylic acid (ASA), probably due to a central mechanism, also implicates changes in the central monoaminergic system. Therefore, we decided to evaluate the antinociceptive interaction between the CB1 receptor agonist, HU210, and ASA in tests involving central pain in rats as well as the implication of the central serotonergic system thereon.

2010 - Trattato Italiano delle Cefalee [Monografia/Trattato scientifico]
Pini, Luigi Alberto; P., Sarchielli; G., Zanchin
abstract

Dal punto di vista scientifico sono notevolmente accresciute le conoscenze sui meccanismi di base delle cefalee, consentendo l'introduzione di nuovi farmaci, mentre altri saranno presto disponibili. Dal punto di vista nosografico, è stata formulata una nuova versione della classificazione internazionale. Anche le linee guida sono state rinnovate, con l'introduzione di nuovi principi attivi e schemi terapeutici, raccolti nell'opera corredati di dosi e modalità di somministrazione. Ogni argomento è affrontato in maniera esaustiva e sono riportate solo conclusioni evidence-based; in caso di reperti contraddittori gli autori assumono una posizione, per aiutare il lettore a raggiungere una conclusione operativa. All'interno di ogni capitolo, schemi e flow chart facilitano la lettura; l'iconografia è costituita da immagini chiare ed esemplificative. Il volume vuole rappresentare un punto fermo nella grande quantità di letteratura prodotta ogni giorno, così da venire incontro alle esigenze del medico che deve dare al singolo malato una risposta diagnostica e terapeutica in tempo reale.

2009 - Future drugs for migraine [Articolo su rivista]
Pini, Luigi Alberto
abstract

Future drug for migraine should work rapidly and consistenlty resolve acute attacks and restore patients to normal life, as well as to reduce the risk ofchronicity. At the time, preventive treatment shuold be aimed to prevent or reverse central sensitization to interrupt the cycle of pain-drug-pain-need of a new drug, that is the main vicious circle for chronic headaches.

2008 - Abnormalities in the cerebrospinal fluid levels of endocannabinoids in multiple sclerosis [Articolo su rivista]
M., Di Filippo; Pini, Luigi Alberto; G. P., Pelliccioli; P., Calabresi; P., Sarchielli
abstract

Objective: Endocannabinoids (eCBs) play a role in the modulation of neuroinflammation, and experimental findings suggest that they may be directly involved in the pathogenesis of multiple sclerosis ( MS). The objective of our study was to measure eCB levels in the cerebrospinal fluid (CSF) of patients with MS.Patients and methods: Arachidonoylethanolamine ( anandamide, AEA), palmotylethanolamide (PEA), 2-arachidonoylglycerol (2-AG) and oleoylethanolamide (OEA) levels were measured in the CSF of 50 patients with MS and 20 control subjects by isotope dilution gaschromatography/mass-spectrometry. Patients included 35 patients with MS in the relapsing-remitting (RR) form of the disease, 20 in a stable clinical phase and 15 during a relapse, and 15 patients with MS in the secondary progressive (SP) form.Results: Significantly reduced levels of all the tested eCBs were found in the CSF of patients with MS compared to control subjects, with lower values detected in the SP MS group. Higher levels of AEA and PEA, although below those of controls, were found in the CSF of RR MS patients during a relapse. Higher levels of AEA, 2-AG and OEA were found in patients with MRI gadolinium-enhancing (Gd+) lesions.Discussion: The present findings suggest the presence of an impaired eCB system in MS. Increased CSF levels of AEA during relapses or in RR patients with Gd+ lesions suggest its potential role in limiting the ongoing inflammatory process with potential neuroprotective implications. These findings provide further support for the development of drugs targeting eCBs as a potential pharmacological strategy to reduce the symptoms and slow disease progression in MS.

2008 - Differential involvement of opioidergic and serotoninergic systems in the antinociceptive activity of N-arachidonoyl-phenolamine (AM404) in the rat: comparison with paracetamol [Articolo su rivista]
Ruggieri, Valentina; Vitale, Giovanni; Pini, Luigi Alberto; Sandrini, Maurizio
abstract

It is recognized that paracetamol undergoes ametabolic transformation to N-arachydonylphenolamine(AM404), a CB1 receptor ligand and anandamide uptakeinhibitor. Using hot-plate and paw pressure tests, wedecided to establish whether AM404 may act throughopioidergic and serotonergic mechanisms. Thus, we pretreatedrats with opioid μ1 (naloxonazine) and κ (MR2266)or 5-HT1A (NAN-190), 5-HT2 (ketanserin), and 5-HT3(ondansetron) receptor antagonists. We investigated thepossible changes in 5-hydroxyindoleacetic acid/serotoninratio in the frontal cortex and pons. The antinociceptiveeffect of AM404 (10 mg/kg, intrapertoneally) or paracetamol(400 mg/kg, intrapertoneally) in either test wasabolished by naloxonazine or MR2266. Ondansetronprevented AM404 activity; NAN-190 and ketanserin wereineffective. Ketanserin antagonized paracetamol activity;NAN-190 and ondansetron were inactive. AM404 did notchange serotonergic activity, while paracetamol decreasedserotonin turnover. The diverse antinociceptive potency ofthe compounds might be explained by the differentinfluence on the serotonergic system, despite a similarinvolvement of opioidergic one.

2008 - Endocannabinoids in platelets of chronic migraine patients and medication-overuse headache patients: relation with serotonin levels [Articolo su rivista]
C., Rossi; Pini, Luigi Alberto; M. L., Cupini; P., Calabresi; P., Sarchielli
abstract

Background Chronic migraine (CM) and medication-overuse headaches (MOH) are well-recognized disabling conditions affecting a significant portion of the headache population attending centers specialized in treating headaches. A dysfunctioning of the serotonergic system has been demonstrated in MOH and CM patients. Here we report on our assessment of the dysfunctioning of the endocannabinoid system as a potential underlying factor in pathogenic mechanisms involved in CM and MOH.Method To test the hypothesis of an impairment in the endocannabinoid system in patients with MOH and CM and to assess its relationship with any disruption of the serotonergic system, we determined the levels of the two main endogenous cannabinoids, anandamide (AEA) and 2-acylglycerol (2-AG), in platelets of 20 CM patients, 20 MOH patients and 20 control subjects and also measured the platelet serotonin levels in the same patients.Result We found that 2-AG and AEA levels were significantly lower in MOH patients and CM patients than in the control subjects, without significant differences between the two patient groups. Serotonin levels were also strongly reduced in the two patient groups and were correlated with 2-AG levels, with higher values for MOH patients.Conclusion These data support the potential involvement of a dysfunctioning of the endocannabinoid and serotonergic systems in the pathology of CM and MOH. These systems appear to be mutually related and able to contribute to the chronification of both CM and MOH.

2008 - Ethano causes neurogenic inflammation and vasodilation by TRPV1 activation and CGRP release in the trigeminovascular system in guinea pig [Relazione in Atti di Convegno]
G., De Siena; P., Nicoletti; M., Trevisani; M., Manconi; G., Zagli; S., Benemei; J. A., Capone; Pini, Luigi Alberto; P., Geppetti
abstract

Ethanol stimulating transient receptor potential vanilloid 1 (TRPV1) on primary sensory neurons promotes release of calcitonin generelated peptide (CGRP)-mediated coronary dilation. Alcohol triggers migraine attacks . We have investigated in guinea pigs whether ethanol by TRPV1 stimulation, causes neurogenic inflammation in the trigeminovascular system. Moreover, Ethanol-evoked release of neuropeptides from slices of dura mater was abolished by capsaicin pretreatment . Intragastric ethanol increased plasma extravasation in dura mater This effect is abolished by capsazepine and SR140333, and by BIBN4096BS, a CGRP receptor antagonist.

2008 - Ethanol causes neurogenic vasodilation by TRPV1 activation and CGRP release in the trigeminovascular system of the guinea pig [Articolo su rivista]
P., Nicoletti; M., Trevisani; M., Manconi; R., Gatti; G., De Siena; G., Zagli; S., Benemei; J. A., Capone; P., Geppetti; Pini, Luigi Alberto
abstract

Ethanol stimulating transient receptor potential vanilloid 1 (TRPV1) on primary sensory neurons promotes neurogenic inflammation, including calcitonin gene-related peptide (CGRP)-mediated coronary dilation. Alcoholic beverages trigger migraine attacks and activation of trigeminal neurons plays a role in migraine. We have investigated in guinea pigs whether ethanol by TRPV1 stimulation causes neurogenic inflammation in the trigeminovascular system. Ethanol-evoked release of neuropeptides from slices of dura mater was abolished by Ca2+ removal, capsaicin pretreatment and the TRPV1 antagonist, capsazepine. Intragastric ethanol increased plasma extravasation in dura mater, an effect abolished by capsazepine and the NK1 receptor antagonist, SR140333, and caused vasodilation around the middle meningeal artery, an effect abolished by capsazepine and the CGRP receptor antagonist, BIBN4096BS. Vasodilation of meningeal vessels by TRPV1 activation and CGRP release may be relevant to the mechanism by which alcohol ingestion triggers migraine attacks.

2008 - Management of patients with primary headache by headache centres improves quality of life [Abstract in Rivista]
F., Granella; A., Bonazzi; Mm, Cainazzo; A., Castellari; Ferrari, Anna; N., Marzocchi; C., Morandi; Pini, Luigi Alberto; E., Sternieri; R., Zucco
abstract

Management of patients with primary headaches by headache specialists improves HRQOL and reduces headache related disability

2008 - Tolerability and efficacy of a combination of paracetamol and caffeine in the treatment of tension-type headache: a randomised, double-blind, double-dummy, cross-over study versus placebo and naproxen sodium [Articolo su rivista]
Pini, Luigi Alberto; E., Del Bene; G., Zanchin; P., Sarchielli; G., Di Trapani; M. P., Prudenzano; G., Lapegna; L., Savi; G., Di Loreto; P., Dionisio; F., Granella
abstract

The main aim of this study was to confirm in an Italian population affected by tension-type headache (TTH) the good profile of safety and tolerability of the combination paracetamol 1,000 mg-caffeine 130 mg (PCF) observed in previous studies, by a comparison with naproxen sodium 550 mg (NAP) and placebo (PLA). A secondary objective was to assess the efficacy of PCF in the acute treatment of TTH. This was a multicentre, randomised, double-blind, double-dummy, crossover, placebo-controlled trial. Tolerability was assessed by recording adverse events by the patient in the 4-h post-dose treatment. To assess the efficacy, the sum of pain intensity differences (SPID) and the total pain relief (TOTPAR) were calculated. Comparing PCF and NAP and PCF and PLA for tolerability, the difference was nonsignificant but the result regarding noninferiority was inconclusive, whilst NAP was noninferior to PLA. As regards SPID and TOTPAR, both PCF and NAP were better than placebo (P &lt; 0.05), but not significantly different from each other. In conclusion, PCF was well-tolerated and effective in the treatment of acute TTH.

2007 - Effect of acute and repeated administration of paracetamol on opioidergic and serotonergic systems in rats. [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Ruggieri, Valentina; Pini, Luigi Alberto
abstract

Objective and design: We investigated the antinociceptiveeffect of paracetamol or morphine after repeatedadministration and the changes in the characteristics of centralμ-, κ- and 5-HT2 receptors.Treatment: Male rats were injected twice a day for sevendays with paracetamol (400 mg/kg, i. p.) or morphine (5 mg/kg, s. c.).Methods: The antinociceptive effect was evaluated 30 minafter single and multiple doses of paracetamol and morphinethrough the hot-plate test. Binding techniques were used toevaluate the receptor characteristics in the frontal cortex.Results: Both paracetamol and morphine induced an antinociceptiveeffect on day 1 but only paracetamol maintainedthis effect for seven days while morphine did not.The number of μ-opioid receptors decreased on days 1, 3,and 7 by a similar percentage after paracetamol administration(by 29, 31 and 34 %, respectively), while morphineproduced a progressive decrease in comparison with controls(by 37, 49 and 60 %, respectively) and κ-opioid receptorswere unaffected. Both drugs similarly decreased the 5-HT2receptor number on all days of treatment (by about 30 %).Conclusions: The opioidergic and serotonergic systems areinvolved in different ways in the induction and maintenanceof antinociception after paracetamol or morphine treatment.

2007 - Endocannabinoids in chronic migraine: CSF findings suggest a system failure [Articolo su rivista]
P., Sarchielli; Pini, Luigi Alberto; F., Coppola; C., Rossi; A., Baldi; M. L., Mancini; P., Calabresi
abstract

Based on experimental evidence of the antinociceptive action of endocannabinoids and their role in the modulation of trigeminovascular system activation, we hypothesized that the endocannabinoid system may be dysfunctional in chronic migraine (CM). We examined whether the concentrations of N-arachidonoylethanolamide (anandamide, AEA), palmitoylethanolamide (PEA), and 2-arachidonoylglycerol (2-AG) in the CSF of patients with CM and with probable CM and probable analgesic-overuse headache (PCM + PAOH) are altered compared with control subjects. The above endocannabinoids were measured by high-performance liquid chromatography ( HPLC), and quantified by isotope dilution gas-chromatography/mass-spectrometry. Calcitonin gene-related peptide (CGRP) levels were also determined by RIA method and the end products of nitric oxide (NO), the nitrites, by HPLC. CSF concentrations of AEA were significantly lower and those of PEA slightly but significantly higher both in patients with CM and PCM + PAOH than in nonmigraineur controls (p &lt; 0.01 and p &lt; 0.02, respectively). A negative correlation was found between AEA and CGRP levels in CM and PCM + PAOH patients (r=0.59, p &lt; 0.01 and r=-0.65, p &lt; 0.007; respectively). A similar trend was observed between this endocannabinoid and nitrite levels. Reduced levels of AEA in the CSF of CM and PCM + PAOH patients may reflect an impairment of the endocannabinoid system in these patients, which may contribute to chronic head pain and seem to be related to increased CGRP and NO production. These findings support the potential role of the cannabinoid (CB) 1 receptor as a possible therapeutic target in CM.

2007 - Increased levels of Neurotrophins are not specific for chronic migraine: Evidence from primary fibromyalgia syndrome [Articolo su rivista]
P., Sarchielli; M. L., Mancini; A., Floridi; F., Coppola; C., Rossi; K., Nardi; M., Acciarresi; Pini, Luigi Alberto; P., Calabresi
abstract

All data obtained in experimental animal pain models support the role of nerve growth factor (NGF) as a putative candidate intervening in the pathogenesis of chronic pain, including chronic daily headache (CDH). Few studies have been carried out to establish its role in maintaining pain states in humans. The present study was aimed at investigating cerebrospinal fluid (CSF) levels of NGF and brain-derived neurotrophic factor (BDNF), both measured by sensitive immunoassay, in 20 chronic migraine (CM) patients and 20 patients affected by primary fibromyalgia syndrome (PFMS), compared with those of 20 age-matched control subjects. Significantly higher levels of both neurotrophins and glutamate were found. A significantly positive correlation emerged between CSF values of BDNF and those of NGF (r =.61, P <.001; r =.53, P <.01) and glutamate (r =.44, P <.02; r =.51, P <.01) in CM and PFMS patients, respectively. These findings suggest the possibility of a NGF-mediated up-regulation of BDNF involved in the pathophysiological events underlying long-term neuroplastic changes in persistent chronic painful conditions, such as CM and fibromyalgia. NGF might indirectly exert its effect through enhancing glutamatergic transmission via BDNF. The above mechanisms could account for sustained central sensitization in both chronic pain states.Perspective: This article presents findings of higher NGF and BDNF levels correlated to increased glutamate levels in the OF of both chronic migraine and fibromyalgia patients. This opens new insights into the pathogenic mechanisms of chronic pain and offers clinicians new therapeutic perspectives targeting the above mechanisms in both painful disorders. (C) 2007 by the American Pain Society.

2006 - A genetic association study of dopamine metabolism-related genes and chronic headache with drug abuse [Articolo su rivista]
S., Cevoli; M., Mochi; C., Scapoli; N., Marzocchi; G., Pierangeli; Pini, Luigi Alberto; P., Cortelli; P., Montagna
abstract

To assess the role of dopamine metabolism-related genes in the genetic liability to chronic headache with drug abuse (DA). We performed a genetic association study using four functional polymorphisms of the dopamine receptor 4 (DRD4), dopamine transporter (DAT), mono-amino-oxidase A (MAOA) and cathecol-O-methyl-transferase (COMT) genes in 103 patients with chronic daily headache associated with DA (CDHDA). Control samples were 117 individuals without headache or DA (controls) and 101 patients with episodic migraine without aura and without DA (MO). No differences were found at the COMT and MAOA genes among the three groups investigated. Allele 4 of DRD4 was significantly overrepresented in patients with MO compared with both controls and CDHDA. Allele 10 of the DAT gene was significantly underrepresented in patients with CDHDA when compared with the MO group. Genetic variability at the DRD4 gene is involved in the predisposition to episodic MO but not to DA, while liability to CDHDA may involve genetic variability at the DAT gene in comparison with episodic MO.

2006 - Clinical-biochemical correlates of migraine attacks in rizatriptan responders and non-responders [Articolo su rivista]
Sarchielli, P; Pini, Luigi Alberto; Zanchin, G; Alberti, A; Maggioni, F; Rossi, C; Floridi, A; Calabresi, P.
abstract

The present study was aimed at verifying the clinical characteristics of a typical attack in 20 migraine patients, 10 responders and 10 non-responders to rizatriptan, and at investigating any differences in the levels of neuropeptides of the trigeminovascular or parasympathetic systems [calcitonin gene-related peptide (CGRP), neurokinin A (NKA) and vasoactive intestinal peptide (VIP) measured by radioimmunoassay methods in external jugular blood] between responders and non-responders. In all responders to rizatriptan, pain was unilateral, severe, and pulsating, and in five of them at least one sign suggestive of parasympathetic system activation was recorded. Five patients who were non-responders to rizatriptan referred bilateral and non-pulsating pain, even though severe in most of them. CGRP and NKA levels measured before rizatriptan administration were significantly higher in responders than in non-responders (P < 0.0001 and P < 0.002, respectively). In the five patients with autonomic signs among rizatriptan responders, detectable VIP levels were found at baseline. One hour after rizatriptan administration, a decrease in CGRP and NKA levels was evident in the external jugular venous blood of rizatriptan responders, and this corresponded to a significant pain relief and alleviation of accompanying symptoms. VIP levels were also significantly reduced at the same time in the five patients with autonomic signs. After rizatriptan administration, CGRP and NKA levels in non-responder patients showed less significant variations at all time points after rizatriptan administration compared with rizatriptan responders. The present study, although carried out on a limited number of patients, supports recent clinical evidence of increased trigeminal activation associated with a better triptan response in migraine patients accompanied by parasympathetic activation in a subgroup of patients with autonomic signs. In contrast, the poor response seems to be correlated with a lesser degree of trigeminal activation, lower variations of trigeminal neuropeptides after triptan administration, and no evidence of parasympathetic activation at baseline.

2006 - Diamo parole al dolore. La percezione del disagio e della difficoltà nella vita quotidiana delle bambine e dei bambini [Curatela]
Pini, Luigi Alberto; L., Restuccia Saitta
abstract

Perché "dare parole al dolore"? Se la concezione normale della vita è quella di provare a stare bene al mondo, realizzarsi, sperimentare la gioia e perseguire il benessere, queste dimensioni si conquistano nel corso di un'intera esistenza, anche incontrando il dolore, che è parte importante della realizzazione della vita emotiva di ognuno.Non si tratta solo del dolore fisico ma della difficoltà di vivere il quotidiano che tocca spesso anche i bambini. Da qui: ansia, paura, stress. Disturbi difficili da comprendere.Il dolore è una dimensione esistenziale che nella vita raggiunge tutti, ma i bambini sono troppo piccoli per prendere su se stessi, consapevolmente, la sofferenza e la difficoltà di vivere. L'infanzia ha troppa poca esperienza di sé e del mondo per affrontare da sola il dolore, per comprenderlo, elaborarlo, accettarlo e condividerlo, ed infine farlo diventare parte della propria storia, connotata anche dalla competenza a reggere la sofferenza.Questo libro raccoglie gli atti di un Convegno Nazionale organizzato dall'Assessorato all'Istruzione e alle Politiche per l'Infanzia, Autonomia Scolastica e Rapporti con l'Università del Comune di Modena, finalizzato all'elaborazione di una dimensione culturale e di un'azione educativa da parte delle figure che, in famiglia e nelle istituzioni, sono a contatto con il dolore dei bambini, in particolare le donne. Perché è quasi sempre delle donne - madri, educatrici, insegnanti, infermiere, ecc. - la cura del dolore e delle sofferenze dei bambini.Il tema del dolore nell'infanzia viene affrontato attraverso discipline diverse - pedagogia, psicologia, filosofia, ecc. - al fine di promuovere un possibile sostegno per coloro che, a vario titolo, si occupano dei bambini aiutandoli ad elaborare percorsi di accettazione positiva/superamento/ricomposizione delle loro esperienze di vita.

2006 - NF-kappa B activity and iNOS expression in monocytes from internal jugular blood of migraine without aura patients during attacks [Articolo su rivista]
P., Sarchielli; A., Floridi; Ml, Mancini; C., Rossi; F., Coppola; A., Baldi; Pini, Luigi Alberto; P., Calabresi
abstract

This study investigated nuclear factor-kappa B (NF-kappa B) activity by electrophoresis mobility gel shift assay and I kappa B alpha expression by Western blot analysis in monocytes obtained from serial samples of internal jugular venous blood taken from seven migraine patients without aura during attacks. Inducible nitric oxide synthase (iNOS) expression was also assessed by reverse transcription-polymerase chain reaction. An increase in NF-kappa B activity peaked 2 h after attack onset. This was accompanied by a transient reduction in I kappa B alpha expression. Up-regulation of iNOS was evident at 4 h, maintained at 6 h and reduced at the end of the attack. These findings substantiate the hypothesis of transitory delayed inflammation, as suggested by the animal model, and suggest the possibility of using therapeutic approaches to target NF-kappa B transcription in the treatment of migraine.

2006 - Switching from HPLC/UV to MEIA for whole blood sirolimus quantitation: Comparison of methods [Articolo su rivista]
Pini, Luigi Alberto; Gallesi, Daniela; Brovia, Daria; Bertolini, Alfio; Pinetti, Diego; Ruggieri, Valentina; Pisa, S; Poppi, B; Castellana, Cn
abstract

Sirolimus is a immunosuppressive agent for renal transplant recipients. Monitoring of whole blood sirolimus concentration is necessary in order to improve clinical outcomes. An increasing number of clinical laboratories (4-14% during 2005) are using microparticle enzyme immunoassay (MEIA) for sirolimus quantitation but previous reports indicated a high variability, with a mean difference of 17% for MEIA method vs. high-performance liquid chromatography/ultraviolet (HPLC/UV). This study was aimed at comparing the reliability of MEIA with the HPLC/UV method. Blood samples from transplant patients were processed using both HPLC/UV and MEIA assays. Comparison and Bland-Altman plots, as well as regression analysis and paired t-test were used to compare results of the assays. Concentrations were stratified into three groups and used to investigate whether any observed difference between methods could be influenced by sirolimus concentration. Regression analysis yielded a coefficient of correlation R of 0.9756, the line of best fit being y = 0.9832x + 0.1976. The statistical analysis showed no difference between the two sets of experimental data. The average percentage difference between the two methods was found to be -0.2 +/- 19.2%. On the basis of our present results, the tested MEIA assay is able to quantify sirolimus concentration with a clinically acceptable imprecision, similar to that of HPLC/UV method.

2006 - Tacrolimus pharmacokinetics in kidney transplant recipients. [Abstract in Rivista]
Ravera, Federica; Cappelli, Gianni; Bonucchi, D.; Davoli, D.; Rubbiani, E.; Savazzi, A. M.; Pini, Luigi Alberto; Albertazzi, A.
abstract

n/a

2005 - A case of a GH-producing pituitary adenoma associated with a unilateral headache with autonomic signs [Articolo su rivista]
N., Marzocchi; Cainazzo, Maria Michela; D., Catellani; Pini, Luigi Alberto
abstract

A 66–year–old man suffered from a drug–resistant, leftsided headache with autonomic signs, triggered by the supine position. The acromegalic facies initially suggested a possible increase in basal plasma levels of GH, but routine haematological controls excluded abnormal values of GH. Cerebral and facial CT scan and MRI did not detect any alterations in the nasal sinuses, except for a mucous cyst. Surgical ablation of the cyst did not alleviate the pain. Further endocrinological tests demonstrated an increase of IGF–1 (somatomedin C), and another MRI scan of the sellar region confirmed the presence of a pituitary macroadenoma on the left paramedian side. After an initial improvement of the symptomatology due to trans–sphenoidal ablation of a benign GH–producing macroadenoma, the headache worsened again. Pain was well correlated with the increased plasma levels of IGF–1. The patient died suddenly for myocardial infarct.

2005 - Endocannabinoid levels in chronic migraine: cerebrospinal fluid findings suggest a failure of this system. [Abstract in Rivista]
Sarchielli, P.; Pini, Luigi Alberto; Rossi, C.; Baldi, A.; Floridi, A.; Calabresi, P.
abstract

n/a

2005 - Experience with the drug information service of the university hospital of Modena [Poster]
Ferrari, Anna; Sternieri, E; Pini, Luigi Alberto; Cainazzo, Mm; Leone, S; Pinetti, D; Bertolini, A.
abstract

The study analizes the activity of the Drug Information Service provided by our Clinical Pharmacology section to the medical staff of the University Hospital of Modena during the last 3 years (2002-2004). The informations most often required concerned interactions (19%), followed by management of drugs during pregnancy (15%), addiction (13%), pharmacokinetics/metabolism/analytical problems (13%). The internal medicine department required the most informations (21%), followed by the infective diseases department (13%).

2005 - High prevalence of patent foramen ovale in migraine with aura [Articolo su rivista]
Ferrarini, G; Malferrari, G; Zucco, R; Gaddi, O; Norino, M; Pini, Luigi Alberto
abstract

In this study we evaluated the presence of patent foramen ovale (PFO) in a cohort of 25 consecutive patients suffering from migraine with aura (MA) during an attack presenting to the emergency ward of an Italian hospital. Patients underwent brain magnetic resonance imaging (MRI) with contrast medium, routine coagulation tests, contrast transcranial echocolour–coded sonography (c–TCCS) and transoesophageal echocardiography (TEE). Of the enrolled patients, 88.7% showed a PFO according to the c–TCCS test, whereas only in 72% TEE confirmed the presence of PFO. This discordance could be due to the fact that c–TCCS is more sensitive even with shunts with minimal capacity also located in the pulmonary vasculature. After surgical treatment of the PFO, MA disappeared within two months. Also, the treatment with warfarin as well as with acetylsalicylic acid and flunarizine was able to dramatically reduce the frequency of migraine attacks. These data indicate a higher prevalence of PFO in MA vs. normal population (OR=2.92) and could suggest that the presence of arteriovenous (AV) shunts could represent a trigger for MA attacks as well as for stroke, but more studies are needed to confirm this preliminary hypothesis.

2005 - Nociceptin/orphanin FQ prevents the antinociceptive action of paracetamol on the rat hot plate test [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Pini, Luigi Alberto; G., Lopetuso; P., Romualdi; S., Candeletti
abstract

Nociceptin/orphanin FQ (N/OFQ) is involved in many behavioural patterns; in particular. it exerts a modulating effect on nociception. Like other proposed antiopiates, nociceptin/orphanin FQ has been shown to have analgesic, hyperalgesic as well as antianalgesic properties. Among the various effects proposed on nociceptive sensitivity at supraspinal level, the antagonistic activity toward morphine analgesia seems to be of interest. Therefore, we decided to investigate whether nociceptin/orphanin FQ and [Arg(14), Lys(15)] nociceptin/orphanin FQ (R-K, a nociceptin analogue) can have the same effect on the analgesia produced by nonopioid analgesics. in this study. we examined the antianalgesic effect of nociceptin/orphanin FQ and its analogue R-K on paracetamol-induced analgesia and evaluated by means of the hot plate test in rats. Nociceptin/orphanin FQ was intracerebroventricularly administered, anti. after 5 min, a dose of 400 mg/kg paracetamol was injected intraperitoneally, 30 min before the hot plate test. Nociceptin/orphanin FQ and R-K showed a dose-dependent antagonism on the antinociceptive effect of paracetamol, and the activity of both drugs was significantly reduced by the antagonist [Nphe(1)] Arg(14), Lys(15)-N/OFQ-NH2 (UFP-101). These data indicate that nociceptin/orphanin FQ and R-K have an antianalgesic effect on the analgesia produced by a nonopioid analgesic drug, like paracetamol, that seems to develop within the brain.

2005 - Risk-benefit and cost-benefit ratio in headache treatment [Articolo su rivista]
Pini, Luigi Alberto; Cainazzo, Maria Michela; D., Brovia
abstract

The cost–benefit and the risk–benefit ratios are two of the most relevant items in ongoing health organisation procedures. The choice of a new or an old therapeutic treatment depends on a number of factors and the evaluation of the cost, in terms of economics, but also in terms of quality of life and type of facilities necessary for one treatment are crucial criteria. Therefore, we have to consider in evaluating treatment strategies not only the activity of a drug in reaching the main end–points, (i.e., pain free or headache relief) but also the safety and perception of safety by patients, and the cost effectiveness, including indirect costs compared with personal and social benefits. Because it is reasonable that a subgroup of migraine patients may have a clinically progressive disorder, studies should be necessary to assess strategies for migraine treatments.

2005 - Topo-kinesthetic memory in chronic headaches. A new test for chronic patients: preliminary report [Articolo su rivista]
Pini, Luigi Alberto; Guidetti, G; Brovia, D; Pontremoli, P; Sarchielli, P.
abstract

The objective of this study was to establish if chronic headaches with medication overuse can modify a topo–kinesthetic memory test. Nineteen patients with medication overuse headache (MOH), 13 patients with chronic tension–type headache (CTTH) without medication use and a group of "normal" subjects underwent a topo–kinesthetic memory test at T0 and after one month (T1); a control group of healthy volunteers was also tested to establish the baseline in our experimental setting. After one month, in the MOH patients there was a reduction of medication overuse from 3.3±2.65 to 1.1±2.23 (p&lt;0.01), but no significant reduction in headache frequency and severity index, quality of life, anxiety and depression scores. The navigation time at T0 was 14.3±4.97, 27.9±10.12, 34.3±15.38 and 7.5±2.33, 10.1±2.95, 11.4±3.21 for control, MOH and CTTH with closed and open eyes, respectively (p&lt;0.02). At T1, the MOH patients reached performances with open eyes similar to the healthy controls, while with closed eyes the navigation test reached times similar to those of CTTH patients. The topokinesthetic memory test seems both able to discriminate MOH and CTTH from healthy volunteers and to be related to pain scores but is not influenced by the use of drugs.

2004 - Different characteristics of triptans [Articolo su rivista]
Pini, Luigi Alberto; Brovia, D.
abstract

Despite the pharmacokinetic differences among triptans and the variety of ways of administration, the clinical differences in everyday use of these drugs do not allow a largely accepted decisional tree. There are a number of comparative trials showing similar results with regard to efficacy, safety, and tolerability of these drugs. This means that the patientrsquos preference is one of the most important decisive factors in choosing one triptan over another. A good migraine therapy requires a balance between patient satisfaction and drug efficacy and safety. All the marked triptans show a good benefit-risk ratio, and comorbidity should be considered when choosing between different triptans.

2004 - OPPIACEI: FARMACOCINETICA, DIPENDENZA, DETOSSIFICAZIONE, TRATTAMENTI AGONISTI ED ANTAGONISTI [Capitolo/Saggio]
G., Baldi; Ferrari, Anna; Gallesi, Daniela; G., Gianelli; S., Manaresi; Pini, Luigi Alberto; Sternieri, Emilio; A., Zannini
abstract

Questo capitolo tratta la farmacodinamica, la farmacinetica, gli impieghi clinici e le procedure di utilizzo degli oppiacei nel trattamento delle dipendenze ed in particolare affronta: metadone, buprenorfina, LAAM (levo alfa acetilmetadolo) e le procedure di disintossicazione nei tossicodipendenti da oppiacei (con e senza farmaci sostitutivi) e il trattamento con antagonisti come il naltrexone.

2004 - Serotonergic and opiatergic modifications induced by paracetamol as a model for daily chronic headache with analgesic overuse [Abstract in Rivista]
Pini, Luigi Alberto; Vitale, Giovanni; Sandrini, Maurizio
abstract

The chronic use of analgesic compounds may contribute to the chronicization of headache. It has been proposed that these headaches associated with daily drug use are due to a rebound effect in a vicious circle drug-headache–drug that mimics drug abuse (Post RM, Silberstein SD, Neurology; 44: 37-4,1994).There are several models to study experimental headaches in relation to acute antimigraine therapy (DeVries et al, Europ J Pharmacol 375: 61-74, 1999), whereas are lacking animal modelsf or daily chronic headache.Paracetamol is a drug widely used to treat headache, and often used in chronic headache sufferers. To explore the possible influence of this drug we performed a study to evaluate the effects of this drug on serotonergic and opiatergic systems in the rat brain after a sub-chronic administration.7 male Wistar rats groups of 8 animals were treated for 7 days with paracetamol i.p. at the dose of 400 mg/kg dissolved in a vehicle volume of 10 ml/kg or vehicle. Animals were submitted to hot-plate test every day at time 2,8 and 24 hours after drug administration. After this test one group of animals was sacrificed every day; the day 1 and 7 also control group were killed. Brains were dissected to determine the presence of binding sites for 5HT2 receptors in cerebral cortex by binding 3H-ketanserin and for opiate receptors by competitive binding with 3H-DAMGO.The results were analysed with Student’s test and Mann-Whitney U test for motor activity. Data were expressed as mean } S.E. Motor activity was not different in vehicle or in paracetamol treated rats at days 1 and 7 ( P> 0.05) . The % of MPE in hotplate test was 5.1}3.2 and 4.7}2.5 at day 1 and 7 for vehicle treated rats, and 24.5}8 and 19.7}4.3 at day 1 and 7 for paracetamol treated rats (P<0.05 vs. ctrl). The maximum bindingcapacity (Bmax )for ketanserin in cortical areas was 254}9.7 and 245}10.5 fmol mg/prot at day 1 and 7 respectively (P>0.5).Paracetamol treated rats Bmax was 194}12.3 and 187}21 fmol mg/prot at day 1 and 7 respectively for ketanserin ( p>0.05), and 250}32 and 170}24 fmol mg/prot at day 1 and 7 respectively for DAMGO (P<0.05). Treatment reduced significantly both types of receptor with respect to vehicle.Repeated doses of paracetamol do not induce tolerance in hotplate test. This treatment induces, as expected, a stable reduction of Bmax in cerebral cortex of 5-HT2 and receptors. These receptors were reduced after a week treatment, whereas the antinociceptive activity was maintained. These data suggest that the prolonged antinociceptive effect of paracetamol is linked more to serotonergic than opiatergic system.This lack of tolerance in analgesic effect of paracetamol could be important to explain the choice of this drug by patients suffering from chronic headaches.

2003 - Chronic daily headache: how to manage it? [Articolo su rivista]
Pini, Luigi Alberto
abstract

This article resumes a lot of information and the literature data on treatment of chronic headacdes, , including in this chapter all daily or near-daily headaches. The treatment proposed ranges from nursing counseling to admission on hospitalized clinic. The sole common item to all authors is the discontinuation of analgesic assumption to increase possibility of reducing headaches by pharmacological, physical or psychological interventions.

2003 - Differential involvement of central 5-HT1B and 5-HT3 receptor subtypes in the antinociceptive effect of paracetamol [Articolo su rivista]
Sandrini, Maurizio; Pini, Luigi Alberto; Vitale, Giovanni
abstract

Objective: We investigated the effect of pre-treatment with ondansetron or CP 93129 (a 5-HT1B agonist) on the antinociceptive activity of paracetamol and the changes in central 5-HT3 receptors induced by paracetamol alone or co-administered with ondansetron. Materials and Subjects: Male Wistar rats (eight per group) were injected with ondansetron (2 and 4 mg/kg s. c.) or CP 93 129 (0.5, 1 and 2 mg/kg s. c.) 15 min before paracetamol (400 mg/kg, i.p.). Methods: Pain threshold was evaluated in the hot-plate or in the paw pressure test 30 min after the last treatment. 5-HT3 receptor binding capacity was measured in the frontal cortex, temporal-parietal cortex and midbrain by means of radioligand binding technique. Statistical analysis was done using ANOVA followed by Student-Newman-Keuls test and 2 X 2 factorial analysis when appropriate. Results: Pre-treatment with ondansetron, at doses of 2 and 4 mg/kg, did not affect the antinociceptive activity of paracetamol in the hot-plate test and in the paw pressure test. Paracetamol did not change the characteristics of 5-HT3 receptors in all the areas investigated. Ondansetron (4 mg/kg s. c) per se significantly increased the 5-HT3 receptor number in the areas used, the effect not being modified by co-administration with paracetamol. On the other hand, CP 93129 (2 mg/kg s. c.) significantly prevented the effect of paracetamol in both algesimetric tests used. Conclusions: Our data indicate that 5-HT1B but not 5-HT3 receptors are involved in the antinociceptive effect of paracetamol in our experimental conditions.

2003 - Homocysteine levels and cardiovascular disease in migraine with aura [Articolo su rivista]
Ferraris, E; Marzocchi, N; Brovia, D; Castellana, Cn; Pini, Luigi Alberto
abstract

Clinical studies suggest that hyperhomocysteinemia could be considered an independent risk factor for premature cerebral, peripheral and vascular diseases. A number of authors found an epidemiological correlation between increased risk of cerebrovascular disease and migraine with aura. In this study, 34 patients suffering from migraine with aura and 36 healthy controls were evaluated with respect to total plasma homocysteine levels, measured with FPIA immunoassay in the fasting state and after methionine load. Moreover, vitamin B12, folate and other classic biochemical indicators of atherosclerosis disease were evaluated. In this study, homocysteine levels, both at basal and after load, and other cardiovascular risk factors such as vitamin B12 and apo-LpA were within the normal range. Other multicentric randomised trials are needed to carry on and confirm these data.

2003 - The genetics of chronic headaches. [Articolo su rivista]
P., Montagna; S., Cevoli; N., Marzocchi; G., Pierangeli; Pini, Luigi Alberto; P., Cortelli; M., Mochi
abstract

Patients with chronic daily headaches (CDH) bear similarities to drug or substance abuse patients, for whom genetic liability loci have been implicated. We reviewed papers dealing with the metabolic and the genetic aspects of CDH. The relative risk for CDH in first-degree relatives is 2.1- to 3.9-fold increased compared to the general population. Genetic variation at the dopamine receptor 2 has been associated with co-morbidity of migraine with aura with major depression and anxiety, and allele D of the angiotensin converting enzyme increases the frequency of migraine without aura attacks. In CDH, analgesic abuse was significantly associated with specific functional polymorphisms at the DRD 4 and at the dopamine transporter (DAT) genes, findings implicating dopamine-related genes in CDH with drug abuse. CDH carries a substantial genetic predisposition. Molecular genetic studies are, however, still few and preliminary.

2003 - Treatment of chronic overmedicated headache patients [Articolo su rivista]
Pini, Luigi Alberto; A., Bertolini
abstract

The effective treatment for chronic headache with analgesic overuse is examined in this review. The first step of treatment is how to stop daily use of the analgesic, supporting the withdrawal syndrome and the worsening headache. In this phase there are different strategies from no treatment to antimigraine drugs. This step is followed by preventive antimigraine treatment sometimes followed or accompanied by antidepressant drug treatment. The most widely used drug in this class is amitriptyline [Tryptizol, Merck & Co, NY, USA. However, newer selective serotonin reuptake inhibitor antidepressants are also proposed. Unfortunately, few good clinical practice studies with long-term follow-up are available. In conclusion, there are no definite guidelines to treat these headaches and probably the main aim of the therapy for these patients should be to enable them to feel in control of their migraine, rather than feeling that migraine or analgesic drugs control them.

2002 - Central antinociceptive activity of acetylsalicylic acid is modulated by brain serotonin receptor subtypes [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Pini, Luigi Alberto
abstract

Male Wistar rats were treated with ondansetron (1 and 2 mg/kg s.c.), ketanserin (0.2, 1 and 5 mg/kg s.c.) or NAN-190 (1, 3 and 5 mg/kg i.p.) 15 min before acetylsalicylic acid (ASA, 400 mg/kg i.p.), and 30 min thereafter the pain threshold was evaluated. The antinociceptive activity of ASA in the hot-plate test was variously affected by ondansetron, ketanserin and NAN-190: at the highest dose (2 mg/kg s.c.) ondansetron abolished it while ketanserin (5 mg/kg s.c.) significantly reduced it, and NAN-190 (1-5 mg/kg) did not significantly modify the effect of ASA. Binding experiments indicate that both ondansetron and ketanserin completely prevented the decrease in the maximum number of 5-HT2 receptors (B-max) provoked by ASA. These data indicate that the central antinociceptive activity of ASA is modulated in a different manner by serotonin receptor antagonists, and that 5-HT2 and 5-HT3 receptors may exert a pivotal role in nociception, alone or in association. Copyright

2002 - Effect of rofecoxib on nociception and the serotonin system in the rat brain [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Pini, Luigi Alberto
abstract

Objective and design: The purpose of the present study was to determine whether the antinociceptive activity of rofecoxib is mediated, at least in part, through changes in the brain serotonergic system. Materials and subjects: Male Wistar rats weighing 180-200 g (groups of eight) were subjected to the hot-plate and formalin tests after rofecoxib, treatment, Cortical areas were removed for serotonin (5-HT) level, 5-HT2 and mu-receptor evaluation. Treatment: Rofecoxib was administered orally at doses of 5, 10, 20 and 50 mg/kg for the time course evaluation in the hot-plate test (30, 60 and 120 min), and at the dose of 10 mg/kg for the formalin test and biochemical determinations. Methods: The tests performed were the hot-plate and the formalin assays. HPLC was used to determine 5-HT levels and radioligand-binding assays were utilized to evaluate the characteristics of 5-HT2 and mu-receptors. The data were analysed by ANOVA or Student's t test. Results: The lowest active dose of rofecoxib in the hot-plate test was 10 mg/kg. The percentage of the maximum possible effect (%MPE) values were: control = 1.7+/-3.4; treated 23.4+/-6.5 (p<6.05). The same dose had a significant effect on both phases of the formalin test. Pretreatment with p-chlorophenylalanine (PCPA) significantly decreased the activity of rofecoxib in the hot-plate test, Rofecoxib treatment increased serotonin levels and decreased the maximum number of 5-HT2 receptors. 5-HT levels (ng/g) were: control = 240.1+/-28.5, rofecoxib = 326.1+/-19.9 in the frontal cortex. The characteristics of mu-receptors did not change. Conclusions: These results suggest that rofecoxib may exert its therapeutic effect, at least in part, through the central serotonergic system. The opioidergic system, on the other hand, seems to be unaffected.

2002 - Trattato delle Cefalee [Monografia/Trattato scientifico]
V., Gallai; Pini, Luigi Alberto
abstract

Il Trattato si pone lo scopo di fornire una visione complessiva dello "stato dell'arte" nel campo delle cefalee per fornire ai neurologi e ai medici italiani uno strumento aggiornato e organizzato dsa consultare in ambulatorio o per approfondire temi di difficoltà clinica o di ricerca.

2001 - Anti-epileptic drugs in the preventive treatment of migraine headache : a brief review. [Articolo su rivista]
Pini, Luigi Alberto; L., Lupo
abstract

This review is aimed to give a comprehensive view on drugs used in the prevention of migraine. At time the most promising drugs are included in the so-called group of anti-convulsive drugs. The mechanism of action of these drugs varies within the class, but a possible common action is believed in reducing the neuronal firing and in the stabilizing membrane potential. The clinical choice within the drugs should take into account the possible side effects of each drug, and relate it to clinical needs and characteristics of patients

2001 - Long-term follow-up of patients treated for chronic headache with analgesic overuse [Articolo su rivista]
Pini, Luigi Alberto; Afg, Cicero; Sandrini, Maurizio
abstract

The study aim is to describe the long-term clinical outcome of 102 chronic headache patients with analgesic daily use. They were assessed for daily drug intake (DDT), headache index (HI) and quality of life (QoL) and compared with a parallel group of patients with active chronic daily headache but no analgesic overuse. For the primary study group, baseline 1995 DDT was 1.80 +/-1.87 and did not differ significantly in 1999. Patients who daily continued to use analgesics had a higher 1995 baseline DDT (t=2.275, P=0.025), a longer drug abuse history (t=2.282, P=0.025) and a higher DDT (t=4.042, P&lt;0.001) 4 years later. At 4 years of follow-up, only one-third of patients initially treated for chronic daily headache and analgesic overuse are successful in refraining from chronic overuse. Those subjects appear to have a persistence for combination analgesic agents; however, their QoL is slightly better than that of patients who revert to episodic headache or continue with chronic daily headache but do not overuse analgesic agents. Persistent analgesic overuse seems to be linked to the length of abuse and to the number of drugs ingested.

2001 - The effect of Paracetamol on nociception and dynorphin A levels in the rat brain [Articolo su rivista]
Sandrini, Maurizio; P., Romualdi; A., Capobianco; Vitale, Giovanni; G., Morelli; Pini, Luigi Alberto; S., Candeletti
abstract

Male Wistar rats were administered with naloxone (1 mg/kg i,p.) or MR 2266 (5 mg/kg i,p) 15 min before paracetamol (400 mg/kg i.p.) treatment and the pain threshold was evaluated. Rats were subjected to the hot-plate and formalin tests and immunoreactive dynorphin A (ir-dynorphin A) levels were measured in the hypothalamus, hippocampus, striatum, brainstem, frontal and parietal-temporal cortex by radioimmunoassay, Pretreatment with naloxone abolished paracetamol antinociceptive activity both in hot-plate and in the first phase, but not in the second phase of the formalin test, while MR 2266 pretreatment was able to antagonise paracetamol effect either in the hot-plate test or in both phases of the formalin test. Among different brain areas investigated paracetamol significantly decreased ir-dynorphin A levels only in the frontal cortex, MR 2266 but not naloxone reversed the decrease in ir-dynorphin A levels elicited by paracetamol. Paracetamol seems to exert its antinociceptive effect also through the opioidergic sistem modulating dynorphin release in the central nervous system (CNS) of the rat, as suggested by the decrease in the peptide levels,

2001 - The effect of paracetamol and morphine combination on dynorphin A levels in the rat brain. [Articolo su rivista]
Sandrini, Maurizio; P., Romualdi; Vitale, Giovanni; G., Morelli; A., Capobianco; Pini, Luigi Alberto; S., Candeletti
abstract

Male Wistar rats were administered with naloxone (1 mg/kg i.p.) or MR 2266 (5 mg/kg i.p) 15 min before paracetamol (400 mg/kg i.p.) treatment and the pain threshold was evaluated. Rats were subjected to the hot-plate and formalin tests and immunoreactive dynorphin A (ir-dynorphin A) levels were measured in the hypothalamus, hippocampus, striatum, brainstem, frontal and parietal-temporal cortex by radioimmunoassay. Pretreatment with naloxone abolished paracetamol antinociceptive activity both in hot-plate and in the first phase, but not in the second phase of the formalin test, while MR 2266 pretreatment was able to antagonise paracetamol effect either in the hot-plate test or in both phases of the formalin test. Among different brain areas investigated paracetamol significantly decreased ir-dynorphin A levels only in the frontal cortex. MR 2266 but not naloxone reversed the decrease in ir-dynorphin A levels elicited by paracetamol. Paracetamol seems to exert its antinociceptive effect also through the opioidergic system modulating dynorphin release in the central nervous system (CNS) of the rat, as suggested by the decrease in the peptide levels.

2001 - Triptans: the experience of a clinical pharmacologist in clinical practice. [Articolo su rivista]
Pini, Luigi Alberto; A. F. G., Cicero
abstract

Despite the pharmacokinetic differences among triptans and the variety of ways of administration, the clinical differences in every day use of these drugs lack in an accepted decisional tree. In fact, there are a number of comparative trials showing conflicting results with regard to efficacy, onset of action, safety and ecurrence incidence. That means that the patient’s preference probably is the main criterion for choosing one triptan vs. others. This point of view is probably correct considering also that the main cause of therapy failure is noncompliance. A good migraine care strategy requires a balance in what the patient views as satisfactory, a reasonable compromise between efficacy and tolerability, and a careful follow-up. Improvement in compliance should be the main and more immediate goal for the treatment of migraine attacks.

2001 - le associazioni del paracetamolo: una nuova frontiera nella terapai del dolore [Monografia/Trattato scientifico]
Pini, Luigi Alberto
abstract

Il libro esaminale associazioni del paracetamolo nella terapia del dolore alla luce delle indicaioni ministeriali volte ad un miglioramento della terapai del dolore anche in Italia

2000 - Relevance of analgesic abuse in the maintenance of chronic headaches [Articolo su rivista]
Pini, Luigi Alberto; G., Relja
abstract

The role of daily use of analgesics is discussed. The literature data are reported and compared with the data collected in the Modena and Trieste Headache Center.

1999 - Efficacy and safety of sumatriptan 50 mg in patients not responding to standard care, in the treatment of mild to moderate migraine [Articolo su rivista]
Pini, Luigi Alberto; Fabbri, L; Cavazzuti, L.
abstract

The tolerability and efficacy of oral sumatriptan 50 mg for the treatment of mild to moderate migraine attacks were assessed in a double-blind, multicenter placebo-controlled study on a group of patients who had not responded sufficiently to analgesic preparations. Three-hundred-and-twenty-eight migraine sufferers treated a first migraine attack with a nontriptan standard care medication: a mixture containing phenazone, butalbital and caffeine (optalidon) or indomethacin plus prochlorperazine plus caffeine (difmetre) or paracetamol 100 mg (tachipirine), depending on their habits. Of these patients, 32.6% reported headache relief with this treatment and were not included in phase ii of the study The 219 patients not reporting relief during the first phase of the study entered the second phase and were randomized to sumatriptan 50 mg or to placebo; 167 of these patients treated a second attack according to the protocol and were evaluated for efficacy: Of the patients with migraine taking sumatriptan, 58% reported headache relief compared with 35% of placebo-treated patients (p = 0.008). The reduction of nausea and vomiting was significantly better in the sumatriptan group. No differences were detected for the recurrence rate, while rescue medication was used more by the placebo group. The safety profile of sumatriptan 50 mg was confirmed. This study demonstrates the usefulness of this dose of oral sumatriptan against the pain and the accompanying symptoms of mild and moderate migraine.

1999 - The potentiation of analgesic activity of paracetamol plus morphine involves the serotonergic system in rat brain [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Ottani, Alessandra; Pini, Luigi Alberto
abstract

Objective and Design: We investigated the antinociceptive effect of subactive doses of paracetamol and morphine, given in combination. Material and Treatment: Male Wistar rats were injected with paracetamol (50 or 100 mg/kg i.p.) and morphine (2, 3 or 5 mg/kg s.c.) 10 min later and subjected to algesimetric tests 20 min thereafter. Methods: Pain threshold was evaluated in the hot-plate and formalin tests. 5-HT2 receptor binding capacity and 5-HT and 5-HIAA levels were measured in cortical and pontine areas of the brain by means of radioligand binding technique and by HPLC, respectively. Statistical analysis was done using Student-Neuman-Keul's test and 2 x 2 factorial analysis. Results: Only when given in combination, paracetamol(100 mg/kg) and morphine (2 and 3 mg/kg) were able to evoke an antinociceptive effect in both tests associated with an increase in 5-HT levels and a decrease in 5-HT2 receptors In the cortex. These effects were prevented by i,p. pretreatment with naloxone (I mg/kg i.p,). Conclusions: Subactive doses of paracetamol and morphine exert an analgesic effect when given in combination in the rat and indicate an involvement of both serotonergic and opiatergic systems.

1998 - Acetylsalicyclic acid potentiates the antinociceptive effect of morphine in the rat:involvement of the central serotonergic system. [Articolo su rivista]
Sandrini, Maurizio; Ottani, Alessandra; Vitale, Giovanni; Pini, Luigi Alberto
abstract

Acetylsalicylic acid and morphine are the most widely distributed and most frequently used drugs in the relief of pain, but their analgesic activity has adverse side-effects. Mixtures containing these two drugs are frequently used to relieve mild to moderate pain despite the paucity of relevant experimental evidence so far published. We set out to study the possible antinociceptive effect of a combination of subactive doses of the two drugs in rats. A combination of low doses of acetylsalicylic acid (50 mg/kg i.p.) and morphine (3 mg/kg s.c.) was administered and the pain threshold was evaluated in the hot-plate and formalin tests, and 5-HT2 receptor binding capacity, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured in the cortex and pontine areas of the brain. The combination of acetylsalicylic acid and morphine had an analgesic effect in both tests that was associated with an increase in 5-HT levels and a decrease in 5-HT2 receptors in the cortex. These effects were either completely abolished or partially prevented by i.p. pretreatment with naloxone (1 mg/kg i.p.). Our results demonstrate that subactive doses of acetylsalicylic acid and morphine can exert analgesic and biochemical effects when given in combination in the rat and suggest an involvement of serotonergic and opiatergic systems.

1998 - Effect of acetylsalicylic acid on formalin test and on serotonin system in the rat brain. [Articolo su rivista]
Pini, Luigi Alberto; Sandrini, Maurizio; Vitale, Giovanni; Ottani, Alessandra
abstract

Acetylsalicylic acid (ASA; 400 mg/kg, i.p.) increased serotonin (5-HT) content in rat brain but did not modify the number or the affinity of 5-HT1A receptors in the pons and the cerebral cortex, whereas the number of cortical 5-HT2 receptors decreased significantly. 2. Pretreatment with parachlorophenylaline (100 mg/kg/day for 4 days) depleted 5-HT brain content but modified neither the serum levels of salicylates nor the 5-HT2 cortical receptor characteristics, and it abolished the antinociceptive effect of ASA, 400 mg/kg, in the first phase of the formalin test. 3. These data support the involvement of the central serotonergic system in the antinociceptive activity of ASA

1997 - Naloxone-reverisble antinociception by paracetamol in the rat. [Articolo su rivista]
Pini, Luigi Alberto; Vitale, Giovanni; Ottani, A; Sandrini, M.
abstract

Paracetamol at the dose of 400 mg/kg i.p. displayed antinociceptive activity in the hot-plate test and the formalin test. Moreover, it induced a significant increase in brain serotonin (5-HT) concentration and a reduction in the number of 5-HT2 receptors in cortical membranes. Pretreatment with naloxone abolished this antinociceptive activity both in the hot-plate test and in the first phase of the formalin test without affecting the serum concentration of paracetamol. At the same time, naloxone prevented the increase in 5-HT concentration in the central nervous system and the reduction in 5-HT2 receptors in cortical membranes. Competition experiments demonstrated that paracetamol possesses affinity for [3H]naloxone binding sites. The action of morphine on nociception and on the serotonergic system was similar to that of paracetamol; all morphine-induced effects were blocked by naloxone. These data provide further evidence for a central antinociceptive effect of paracetamol and support the hypothesis that paracetamol exerts its antinociceptive activity through the serotonergic system. Moreover, our results point to the relationship between serotonergic and opiatergic systems in the antinociceptive activity of paracetamol.

1997 - Serotonin and opiate involvement in the antinociceptive effect of acetylsalicylic acid [Articolo su rivista]
Pini, Luigi Alberto; Vitale, Giovanni; Sandrini, Maurizio
abstract

Acetylsalicylic acid (ASA), 400 mg/kg i.p., displayed antinociceptive activity in both the hot-plate and the formalin test, ASA significantly increased brain serotonin (5-HT) content and reduced the number of 5-HT2 receptors in cortical brain membranes 30 min after drug administration, Pretreatment with naloxone abolished the antinociceptive activity of both ASA and morphine in the hot-plate and formalin tests and prevented the increase in cerebral 5-HT concentration and the reduction in 5-HT2 receptors in cortical membranes induced by ASA, The serum salicylate concentrations were not affected by pretreatment with naloxone, These data indicate a central antinociceptive activity of ASA and suggest that ASA may exert its antinociceptive action through serotonergic and opiatergic pathways.

1996 - Headaches associated with chronic use of analgesics: A therapeutic approach [Articolo su rivista]
Pini, Luigi Alberto; M., Bigarelli; Vitale, Giovanni; Sternieri, Emilio
abstract

We evaluated 102 patients attending the Headache Study Center of the University of Modena who were suffering from chronic daily headache with daily drug intake. Patients underwent either day hospital treatment followed by a standard prophylactic therapy or they started prophylactic therapy immediately. After 30 and 120 days, both the Headache Index and the daily drug intake had significantly improved (P<0.001), and there were no differences in reduction of mean values of the Headache Index or daily drug intake with respect to the two treatments, nor with regard to the prophylactic therapy chosen. Twenty-eight percent of patients reverted to daily drug intake after a 4-month follow-up; these patients took barbiturate-containing mixtures in a higher percentage than other drugs, and within the group of relapsing patients the outpatients relapsed to analgesic intake more than the day hospital-treated patients (P<0.05).

1996 - The antinociceptive action of paracetamol is associated with changes in the serotonergic system in the rat brain [Articolo su rivista]
Pini, Luigi Alberto; Sandrini, Maurizio; Vitale, Giovanni
abstract

The antinociceptive activity of paracetamol in the hot plate and formalin tests was studied to establish the relationship between antinociceptive activity and the central serotonergic system. Significant antinociceptive activity of paracetarnol was observed in the formalin test at the dose of 300 mg/kg, while, at the dose of 400 mg/kg, the drug was active both in the formalin and in the hot-plate test. Serum paracetamol levels remained sub-toxic and the behavioral profile remained unchanged. Depletion of brain serotonin with p-chlorophenylalanine prevented the antinociceptive effect of paracetamol in the hot-plate test and in the first phase of the formalin response. Paracetamol significantly increased the serotonin content in the pontine and cortical areas (by 75 and 70%, respectively). The pretreatment with p-chlorophenylalanine reduced the 5-hydroxytryptamine (5-HT) content in cortical and pontine areas to 12 and 19% of baseline values, respectively, and prevented the enhancement induced by paracetamol. The maximum number of cortical 5-HT2 receptors was reduced by paracetamol, while the number of 5-HT1A receptors in both cortical and pontine areas was unchanged. Pre-treatment with p-chlorophenylalanine prevented the reduction in the number of 5-HT2 receptors induced by paracetamol. These results provide evidence for the involvement of the central serotonergic system in the antinociceptive effect of paracetamol in the hot plate and formalin tests.

1995 - EFFECTS OF ACETYLSALICYCLIC ACID ON SEROTONIN BRAIN RECEPTOR SUBTYPES [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; M., Dondi; Pini, Luigi Alberto
abstract

1. The lysine salt of acetyl salicylic acid (ASA) at a dose equivalent to 400 mg/kg of acetyl salicylic acid (ASA) was intraperitoneally administered in rats. 2. After 30 and 120 min ASA did not modify the number of receptors nor the affinity of [H-3] 8-OH-DPAT binding sites in pens and cerebral cortex. On the other hand, the receptor number in the cortex membranes decreased significantly using [H-3] ketanserin as ligand, while the receptor number in the pontine membranes did not change. 3. These data support the involvement of central 5-HT receptors in the mode of action of ASA.

1995 - HIGH EFFICACY AND LOW-FREQUENCY OF HEADACHE RECURRENCE AFTER ORAL SUMATRIPTAN [Articolo su rivista]
Pini, Luigi Alberto; Sternieri, E; Fabbri, L; Zerbini, O; Bamfi, F; Mamoli, A; Solime, F; Saginario, M; Petromilli, M; Bonuccelli, U; Nuti, A; Desimone, G; Digregorio, R; Rossi, F; Blasi, F; Bernardini, C; Lorusso, F; Dibattista, Gc; Carratelli, D; Castorina, F; Cam,
abstract

This multicentre, double-blind study compared (100 mg) sumatriptan administered orally with placebo in treating an acute attack of migraine; 238 patients were studied over a 48-h period. Four hours after treatment, 92 of the 142 evaluable sumatriptan patients (65%) showed significant reductions (P &lt; 0.001) in headache severity, clinical disability and accompanying symptoms compared with 32 of the 80 evaluable placebo-treated patients (40%). The duration of attack prior to taking medication and the history of persistent migraine do not influence the observed difference between the two treatment regimens (sumatriptan and placebo), which remained statistically significant (P &lt; 0.001) in both cases. The incidence of headache recurrence in patients who experienced relief 4 h after initial treatment was low, occurring in 16 (17%) and 4 (13%) of the sumatriptan- and placebo-treated patients, respectively. Only patients with a history of migraine attacks lasting longer than 24 h suffered headache recurrences, and these recurrences were not consistent with the International Headache Society definition of migraine. Treatment with sumatriptan was well tolerated.

1995 - Involvement of brain serotonergic system in the antinociceptive action of acetylsalicylic acid in the rat [Articolo su rivista]
Pini, Luigi Alberto; M., Sandrini; Vitale, Giovanni
abstract

The pain-threshold in the hot-plate test and serotonin (5-HT) receptor binding capacity in the cortex and pontine areas of rat brain were studied after intraperitoneal (ip) administration of acetyl salicylate of lysine equivalent to 400 mg/kg of acetylsalicylic acid (ASA). The antinociceptive activity of ASA was prevented by ip pre-treatment with Parachlorophenylalanine (PCPA) at the rate of 100 mg/kg/day for 4 days. PCPA pre-treatment increased the number of 5-HT receptors and abolished the ASA-induced reduction in 5-HT receptor binding capacity in the cortex but did not affect serum salicylate levels. These results provide support for the hypothesis that the antinociceptive action of ASA, at least in the hot-plate test, involves the central serotonergic system.

1995 - Lack of activity of azapropazone in the hot-plate test and in 5-HT1A and 5-HT2 receptor subtypes in rat brain membranes [Articolo su rivista]
Pini, Luigi Alberto; Sandrini, Maurizio; Vitale, Giovanni
abstract

This study aimed to investigate the antinociceptive activity of azapropazone (AZA), a weak prostaglandin synthesis inhibitor using the hot-plate test, and its ability to modify the serotonin-binding capacity in rat brain membranes. it revealed that AZA had no antinociceptive effect in the hot-plate test at the doses of 400 and 600 mg/kg when orally administered (p.o.), and at 400, 500 and 600 mg/kg after intraperitoneal injection (i.p.). At the dose of 600 mg/kg i.p. the drug failed to modify the number and the affinity of 5-HT1A and 5-HT2 receptors in rat brain membranes. in accordance with our previous findings on a positive correlation between NSAIDs antinociception in this experimental model and changes in 5-HT receptor characteristics, these results suggest an association between the lack of AZA-mediated antinociception in the hot-plate test and the drug's inability to modify the characteristics of 5-HT1A and 5-HT2 receptor binding sites in rat brain membranes.

1994 - DOES CHRONIC USE OF SUMATRIPTAN INDUCE DEPENDENCE [Articolo su rivista]
Pini, Luigi Alberto; Trenti, T.
abstract

The paper compare the pharmacological activities of sumatriptan in animal models aimed to evaluate a possible activity in induce abituation and repeated use. On the other hand, are reported clinical data suggesting a possible psychological dependence in patent using sumatriptan daily or near daily.

1994 - Glycyrrhizin and 18 beta-glycyrrhetinic acid: a comparative study of the pharmacological effects induced in the rat after prolonged oral treatment. [Articolo su rivista]
Rossi, T; Vampa, G; Benvenuti, Stefania; Pini, Luigi Alberto; Galatulas, I; Bossa, R; Castelli, M; Ruberto, Ai; Baggio, G.
abstract

Recent clinical and toxicological studies have investigated the mineralcorticoid-like and hypertensive effects of liquorice, and we therefore set out to identify the active component responsible for these effects. We conducted a 30-day comparative analysis of glycyrrhizin and 18 beta-glycyrrhetinic acid and found that the latter causes significant variations both in systolic blood pressure and in the excretion in the urine of Ca++. The effects were fully reversible on suspension of treatment.

1994 - INTERNATIONAL-HEADACHE-SOCIETY CLASSIFICATION - INTEROBSERVER RELIABILITY IN THE DIAGNOSIS OF PRIMARY HEADACHES [Articolo su rivista]
Granella, F; Dalessandro, R; Manzoni, Gc; Cerbo, R; Damato, Cc; Pini, Luigi Alberto; Savi, L; Zanferrari, C.
abstract

We assessed interobserver reliability of the International Headache Society (IHS) classification for diagnosis of primary headaches. The study was performed on 103 patients consecutively seen at two Headache Centres. Each patient was given a structured interview recorded on videotape. Four experienced clinicians then reviewed the interviews separately and made a diagnosis of headache according to IHS criteria at the one- and two-digit levels. At both the one- and the two-digit level the agreement was substantial (Kappa = 0.74 and 0.65, respectively). The analysis of reliability for each of nine items necessary for diagnosis showed an agreement ranging from substantial (Kappa = 0.69) to almost perfect (Kappa = 0.89). Our results indicate that the IHS classification has a good reliability for the diagnosis of primary headaches at the one- and two-digit levels.

1994 - Lack of activity of Ketorolac in hot-plate test and serotonin binding capacity of brain membranes in rats [Articolo su rivista]
Vitale, Giovanni; Sandrini, Maurizio; Pini, Luigi Alberto
abstract

An increasing number of observations indicate that prostaglandin synthesis inhibition is not a satisfactory explanation for the antinociceptive activity of the non-steroidal anti-inflammatory drugs. In the hot-plate test performed 1 or 2 h after ketorolac at 40, 70 and 100 mg/kg i.p., the drug does not display any significant antinociceptive activity. Nor, at the two higher doses used, does it affect the cortical and pontine serotonin binding capacity of rat brain membranes 2 h after treatment. The data suggest that this lack of antinociceptive activity in the hot-plate test is associated with the drug's inability to affect the central serotoninergic system.

1993 - Disposition of naproxen after oral administration during and between migraine attacks. [Articolo su rivista]
PINI, Luigi Alberto; BERTOLOTTI, Marco; Trenti, T; VITALE, Giovanni
abstract

Naproxen is an anti-inflammatory drug widely used in the management of pain and in the treatment of migraine and headache. As gastrointestinal disturbances are a common feature of migraine, the aim of this study was to evaluate the absorption and the efficacy of naproxen administered during migraine attacks. Ten patients were treated with 500 mg of a soluble form of naproxen during and between migraine attacks. Clinical parameters and drug plasma levels were recorded at scheduled times. Pain reduction, from severe to mild was evident by 6.5 +/- 3.4 hours and the total pain score showed a reduction from 2 hours onwards. Pharmacokinetic data showed a slight delay in drug absorption during attacks (absorption half-life and time of maximum drug concentration were increased during attacks), but overall bioavailability of naproxen, as reflected by area under the curve (AUC) and maximum plasma drug concentration were unchanged. Since pain relief was reported, it may be concluded that delayed absorption has little or no influence on the therapeutic effect of naproxen in migraine attacks in fasting patients.

1993 - Effects of chronic treatment with phenazone on the hot plate test and [3H]-Serotonin binding sites in pons and cortex membranes of the rat [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Pini, Luigi Alberto; E., Sternieri; Bertolini, Alfio
abstract

Many reports indicate that nonsteroidal anti-inflammatory drugs exert their antinociceptive effect through adrenergic and serotoninergic systems. We investigated the acute and chronic effects of phenazone on the pain threshold and on brain serotonin binding sites. A relationship between phenazone serum levels and the antinociceptive effect was found; acute treatment with phenazone provokes a significant decrease in serotonin binding sites both in the pons and cerebral cortex after 2, 4 and 8 h, but not after 24 h. After 15 and 30 days of treatment, the number of binding sites increases both in the pons and cortex.

1993 - THE ROLE OF SEROTONIN BRAIN RECEPTORS IN THE ANALGESIC EFFECT OF PHENAZONE [Articolo su rivista]
Pini, Luigi Alberto; Vitale, Giovanni; Sandrini, Maurizio
abstract

The effects of treatment with para-chloro-phenyl-alanine (PCPA) (100 mg/kg i.p. for 4 days) were studied on the hot-plate test and on brain 5-HT binding in phenazone treated rats. Phenazone per se induces analgesia in the hot-plate test and decreases the number of cortical and pontine 5-HT binding sites. A pre-treatment with PCPA prevents both the analgesic effect and the reduction of 5-HT binding sites caused by phenazone. These data suggest that the brain serotonin system may play a role in phenazone-induced antinociception.

1993 - The decrease in plasma thiol groups in daily headache paracetamol abuser patients as possible factor of pain maintenance [Abstract in Rivista]
Trenti, T; Bertolotti, Marco; Ferrari, Anna; Pini, Luigi Alberto; Sternieri, E.
abstract

We have assessed plasma GSH in patients using paracetamol daily. In these patients a significant lower plasma GSH concentration was found with respect to controls. After the i.v. administration of GSH free plasma cysteine was 12 fold higher than in basal condition and all the pattern of plasma thiol groups was modified. This work suggests that the possible protective effect of GSH administration is due to the availability of plasma thiol compounds that enter the cell rather than GSH itself.

1992 - BRAIN-SEROTONIN BINDING-CAPACITY, ANALGESIA AND DRUG SERUM LEVELS AFTER ACUTE TREATMENT WITH PHENAZONE IN RATS [Articolo su rivista]
Pini, Luigi Alberto; Vitale, Giovanni; Sandrini, Maurizio
abstract

Phenazone induces analgesia in the hot-plate test and decreases the number of cortical and pontine 5-HT binding sites A pre-treatment with PCPA prevents both the analgesic effect and the reduction of 5-HT binding sites caused by phenazone. These data suggest that the brain serotonin system may play a role in phenazone-induced antinociception.

1992 - PHARMACOKINETIC OF REDUCED GLUTATHIONE IN MAN - EFFECT ON PLASMA CYSTEINE AND THIOL COMPOUNDS [Articolo su rivista]
Trenti, T; Bertolotti, Marco; Ferrari, Anna; Pini, Luigi Alberto; Sternieri, E.
abstract

No abstract available

1992 - PHARMACOKINETICS OF NAPROXEN AFTER ORAL-ADMINISTRATION DURING AND OUT OF MIGRAINE ATTACKS [Articolo su rivista]
Pini, Luigi Alberto; Bertolotti, Marco; Trenti, T; Sternieri, E.
abstract

Naproxen is an anti-inflammatory drug widely used in the management of pain and in the treatment of migraine and headache. As gastrointestinal disturbances are a common feature of migraine, the aim of this study was to evaluate the absorption and the efficacy of naproxen administered during migraine attacks. Clinical parameters and drug plasma levels were recorded at scheduled times. Pain reduction, from severe to mild was evident by 6.5 +/- 3.4 hours and the total pain score showed a reduction from 2 hours onwards. Pharmacokinetic data showed a slight delay in drug absorption during attacks (absorption half-life and time of maximum drug concentration were increased during attacks), but overall bioavailability of naproxen, as reflected by area under the curve (AUC) and maximum plasma drug concentration were unchanged. Since pain relief was reported, it may be concluded that delayed absorption has little or no influence on the therapeutic effect of naproxen in migraine attacks in fasting patients.

1992 - PHYSIOLOGICAL-PARAMETERS AND PLASMA-LEVELS AFTER SHORT AND LONG-TERM PROPOFOL INFUSION [Articolo su rivista]
Vitale, Giovanni; Pini, Luigi Alberto; Bertellini, E.
abstract

After IV bolus elimination of propofol is slower than previously reported. After prolonged i.v. infusion of propofol values of elimination half-life ranged widely from 12- to 40 h. , systemic clearance from 1.42 to 1.86 l h-1 and volume of distribution were similar to those obtained with bolus administration. The large volume of distribution is consistent with the high octanol/blood partition coefficient, which was found to be 72.0. Despite the long elimination half-life, blood propofol concentrations appeared to approach steady state within 30 min . This is because this drug displays multicompartment pharmacokinetics, whereas the long elimination half-life of propofol is probably of little significance in designing infusions regimens

1992 - Plasma glutathione level in paracetamol daily abuser patients. Changes in plasma cysteine and thiol groups after reduced glutathione administration [Articolo su rivista]
Trenti, T; Bertolotti, Marco; Castellana, Cn; Ferrari, Anna; Pini, Luigi Alberto; Sternieri, Emilio
abstract

Since plasma reduced glutathione (GSH) seems to reflect liver GSH content, we have assessed plasma GSH in patients using paracetamol daily. In these patients a significant lower plasma GSH concentration was found with respect to controls. After the i.v. administration of GSH free plasma cysteine was 12 fold higher than in basal condition and all the pattern of plasma thiol groups was modified. This work suggests that the possible protective effect of GSH administration is due to the availability of plasma thiol compounds that enter the cell rather than GSH itself.

1992 - The effect of chronic treatment with phenazone on [3H]-serotonin binding sites in pons and cortex membranes of the rat [Articolo su rivista]
Vitale, Giovanni; Pini, Luigi Alberto; Sandrini, Maurizio
abstract

We studied 36 male rats, 18 o them were trated orally for 30 days with 60 mg/kg/day of phenazone and 18 used as controls. Our data show that a chronic treatment with phenazone increases the number of serotonin receptors in two brain areas while the affinity is not modified; in the same model we demonstrated that phenzone modifies noradrenergic pontine receptors. The role of these changes in receptors characterstics after a long-term treatment with phenazone may contribute to the antinociceptive effect of phenazone.

1991 - Chronic treatment with phenazone modifies pontine noradrenergic receptors in rats. [Capitolo/Saggio]
Pini, Luigi Alberto; Vitale, Giovanni; Sandrini, M.
abstract

N/A

1991 - DAPIPRAZOLE COMPARED WITH CLONIDINE AND A PLACEBO IN DETOXIFICATION OF OPIATE ADDICTS [Articolo su rivista]
Pini, Luigi Alberto; Sternieri, E; Ferretti, C.
abstract

The activity of dapiprazole, clonidine and a placebo were studied to reduce abstinence symptoms and modify the psychological outline during a withdrawal period in heroin addicts. Forty heroin addicts were treated in a double-blind design and, within two weeks, relapse in heroin use was higher in the placebo group (8/10) in comparison with the dapiprazole (1/20) and clonidine (0/10) groups. During treatment clonidine was able to reduce depression and paranoid-ideas scores, whereas dapiprazole reduced depression, anxiety, hostility, phobic anxiety, obsessiveness and psychoticism. Side-effects were mild and it may be concluded that both dapiprazole and clonidine are effective and safe drugs for the treatment of opiate withdrawal syndrome.

1991 - DETERMINATION OF NALTREXONE AND 6-BETA-NALTREXOL IN PLASMA BY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY WITH COULOMETRIC DETECTION [Articolo su rivista]
Zuccaro, P; Altieri, I; Betto, P; Pacifici, R; Ricciarello, G; Pini, Luigi Alberto; Sternieri, E; Pichini, S.
abstract

A simple and reliable reversed-phase high-performance liquid chromatographic method with coulo-metric detection is described for the quantitation of naltrexone and its metabolite, 6-beta-naltrexol, in plasma samples of healthy volunteers who received orally 50 mg of naltrexone. The analytes and the internal standard, naloxone, are extracted with an octadecyl solid-phase extraction column before chromatography. The mobile phase is 0.01 M potassium phosphate (pH 3)-acetonitrile (85:15, v/v) and it is pumped at 0.8 ml/min. The coulometric detector is formed by two electrodes set at +0.20 V and +0.70 V, with a palladium reference electrode. The limit of quantitation observed was 5 ng/ml for both naltrexone and 6-beta-naltrexol. This method can be used to investigate pharmacokinetic parameters of different pharmaceutical preparations of this opioid antagonist.

1991 - Effects of long-term treatment with naltrexone on hepatic enzyme activity. [Articolo su rivista]
Pini, Luigi Alberto; Ferretti, C; Trenti, T; Ferrari, Anna; Sternieri, E.
abstract

The influence of naltrexone on liver function in heroin addicts was studied, with respect to the metabolizing function by using the antipyrine clearance and to cellular damage by monitoring plasma levels of hepatic enzymes. The clearance of antipyrine was not affected by naltrexone treatment, and, during the study period, the use and withdrawal of benzodiazepines and alcohol did not change this parameter; moreover, there was no relationship between changes in plasma hepatic enzymes and antipyrine half-life. Mean plasma levels of hepatic enzymes did not show significant modification in the course of treatment with naltrexone.

1991 - Interactions between chronic headache and analgesic drug overuse: clinical and toxicological aspects [Articolo su rivista]
Ferrari, Anna; Bertolotti, Marco; Malferrari, G; Pini, Luigi Alberto; Trenti, T; Sternieri, E.
abstract

Usually overuse of analgesic drugs in chronic headache sufferers is seen only as a secondary or accesssory event complicating headache. We instead believe that the two phenomena are closely interrelated, so to generate a "loop" from which important clinical and toxicologial implication can derive. On the basis of these considerations the aim of our research was to descrive the complex interactions between patient, chronic headache and analgesic drug. The combination of indomethacin plus caffeine plus prochlorperazine, and triptans were the medications most frequently overused by our patients; only a few patients overused ergot preparations. The majority of patients used the same type of drug daily. All patients referred they increased the frequency of self-medication because the headaches were getting worse. For most patients medication overuse made the headache more endurable, thus allowing them to work orfunction more or less normally in daily life. Only a minority experiencedwithdrawal symptoms after discontinuation of the medication overuse. After detoxification, antidepressants were the class of drugs most used for prophylaxis.

1991 - Modalità d’uso e tossicità delle associazioni analgesiche nei soggetti con cefalea cronica quotidiana [Relazione in Atti di Convegno]
Ferrari, Anna; Giroldi, L; Malferrari, G; Bergonzini, G; Pini, Luigi Alberto; Sternieri, E.
abstract

Nella nostra casistica i soggetti che soffrono di cefalea cronica ed usano quotidianamente analgesici hanno un’età media di 51 anni anche se il range è ampio (20-70 anni); sono soprattutto pazienti di sesso femminile (F/M=4:1) che dicono di aver sofferto all’esordio di una cefalea episodica (91%); usano prevalentemente OTC (58%) e assumono in maggioranza associazioni analgesiche contenenti più principi attivi (89%); il 64.7% dice di utilizzare sempre un solo tipo di analgesico ma il 68% assume almeno due dosi al giorno. La maggioranza (84%) dice di assumere l’analgesico per poter far fronte alle attività quotidiane nonostante la cefalea; il 70% dei pazienti continua nell’uso dell’analgesico nonostante la presenza di effetti collaterali che riconosce come esacerbati da tale uso. Circa il 39% dei pazienti riferisce di aver tentato ripetutamente di ridurre o interrompere l’assunzione di farmaci analgesici senza riuscirvi (36). Le persone che soffrono di cefalea cronica sono soggette ad una grande polimedicazione: oltre l’82% assume anche farmaci di altre categorie terapeutiche: antipertensivi, antiulcera, procinetici, tranquillanti, lassativi, antidepressivi, ed altri ancora. Il 55 % soffre di disturbi organici concomitanti (gastropatie, ipertensione, anemia, tiroidite, insufficienza renale cronica, stipsi) e il 65% ha comorbidità psichiatrica, soprattutto depressione (46).

1991 - Pharmacological outline of chronic headache patients: overlap between depressive and nociceptive symptomatology [Capitolo/Saggio]
Sternieri, Emilio; Guaraldi, Gp; Mazzi, Fausto; Venuta, Marco; Orlandi, Emanuele; Trenti, T; Bertolotti, Marco; Ferrari, Anna; Pini, Luigi Alberto
abstract

This book is a collection of 30 chapters of widely varying subject matter—the unifying theme being that these chapters deal with depression, headache, or both. Sections include the following: neurochemistry of 5-hydroxytryptamine pathways, with four excellent chapters on this subject and review of findings as they relate to headache, depression, and pain; chronic headache and mood disorders, four primarily clinical chapters with a brief, interesting review of pain threshold studies; periodicity of affective and headache disorders, with chapters on seasonal cycles found in depression, menstrual cycles in mood and headache, and effects of different treatments; drugs affecting the serotonergic system (seven chapters of widely varying quality) with three review articles, one (by Sicuteri) giving a summary of his overall formulation of central pain systems, another summarizing data on serotonin and depression, and three subsequent studies briefly reporting results on specific pharmacologic agents

1991 - Plasma glutathione level in chronic headache drug abuser patients [Articolo su rivista]
T., Trenti; Ferrari, Anna; Pini, Luigi Alberto; G., Sancez; G., Nappi; E., Sternieri
abstract

Plasma reduced glutathione (GSH) seems to reflect liver GSH content, we have assessed plasma GSH in patients with chronic headaches. We found a significant lower plasma GSH concentration was found with respect to controls. We teste a administartion of GSH IV and found that.v. GSH free plasma cysteine was 12 fold higher than in basal condition and all the pattern of plasma thiol groups was modified. This work suggests a possible protective effect of GSH administration in Chronic Headache patients.

1991 - Plasma reduced glutathione level and changes in thiol groups after glutathione administration in drug abuser patients - [Articolo su rivista]
T., Trenti; L., Pagliani; Vitale, Giovanni; Pini, Luigi Alberto; B., Botti; V., Vannini; Sternieri, Emilio
abstract

N/A

1991 - Significato biologico e possibili applicazioni cliniche del glutatione [Capitolo/Saggio]
Trenti, T; Pini, Luigi Alberto; Pagliani, L; Ferrari, Anna; Sternieri, E.
abstract

Il glutatione è stato caratterizzato strutturalmente nel 1929 come un tripeptide formato da acido glutammico, cisteina, glicina. E' indicato con la sigla GSH poichè le sue funzioni biologiche sono principalmente associate alla presenza del gruppo sulfidrilico della cisteina che ne determina la forma attiva e lo differenzia dalla forma ossidata indicata come GSSG. In molte cellule il GSH rappresenta più del 90% dei gruppi sulfidrilici non proteici ed è pertanto il più abbondante peptide a basso peso molecolare. Il fegato sembra essere il più grande produttore e consumatore di GSH ridotto. Il GSH è il principale composto tiolico presente nel SNC dove raggiunge la massima concentrazione nella corteccia. Si ritiene che il glutatione sia importante nel determinare l'inizio e la progressione dei meccanismi di attivazione linfocitaria svolgendo quindi un ruolo nella difesa immunitaria.

1991 - Urinary neopterin in malignant lymphoma [Articolo su rivista]
Piccinini, Lino; Zironi, S.; Federico, Massimo; Pini, Luigi Alberto; Luppi, G.
abstract

Urinary neopterin levels were studied in 96 patients with malignant lymphomas. Twenty-eight had Hodgkin's disease and 68 non-Hodgkin's lymphoma. Neopterin excretion was significantly related to the clinical stage of the disease. Mean neopterin excretion in patients with active disease (634 +/- 527 mumol neopterin/mol creatinine) was significantly higher (p = 0.000) than in patients in complete remission (198 +/- 105 mumol neopterin/mol creatinine). Mean neopterin levels of patients in stage III-IV were higher than for patients in stage I-II. These findings were the same in patients with Hodgkin's disease and those with non-Hodgkin's lymphoma (659 +/- 593-425 +/- 316 mumol neopterin/mol creatinine), regardless of the histological subtype. A significant correlation was found between neopterin excretion, ESR (r = 0.31; p = 0.003) and hemoglobin (r = -0.40; p = 0.000). Longitudinal analysis showed a trend towards a correlation between response to therapy and neopterin excretion. These findings suggest that neopterin may be a useful prognostic marker in non-Hodgkin's lymphoma.

1990 - Active reporting scheme: an example to evaluate specific adverse drug reactions. [Relazione in Atti di Convegno]
Pini, Luigi Alberto; Sternieri, E.
abstract

The post-marketing drug-surveillance is mainly based upon spontaneous reporting, whereas in Italy there are a very little percentage of doctors who fill the ADR forms. To increase this percentage we activated an active reporting protocol in out ward. We limited the survey to NSAIDs to improve attention and the doctor's compliance. After an active training period the % of item filled was 95% and there was no differences after a 6 month interval. The % of ARD were 0.27% and 0.21% of DDD in the first and second period respectively.

1990 - PHARMACOKINETICS OF TIAPROFENIC ACID AFTER ORAL-ADMINISTRATION IN FASTING PATIENTS DURING AND BETWEEN MIGRAINE ATTACKS [Articolo su rivista]
Pini, Luigi Alberto; Bertolotti, Marco; Bergonzini, G; Casalgrandi, L; Giroldi, L; Sternieri, E.
abstract

This study examined the pharmacokinetics of 300 mg of tiaprofenic acid, a NSAID belonging to the 2-arylpropionic class, as a single oral dose, in 10 migraine patients during and out of migraine attacks. Plasma concentration of tiaprofenic acid was determined by HPLC analysis. Drug absorption appeared to be the same during and out of migraine attacks (absorption half life: during attack, 0.249 +/- 0.122 hr; out of attack, 0.249 +/- 0.105 hr; maximum plasma concentration: during attack, 37.8 +/- 9.8 ug/ml; out of attack, 40.1 +/- 13.2 ug/ml). The other pharmacokinetic parameters evaluated were not affected by headache attacks as well. We conclude that tiaprofenic acid absorption and metabolism are not affected by migraine attacks. Also, our data suggest that tiaprofenic acid might be useful in the treatment of migraine

1990 - Protocollo di studio del sodiocromoglicato (SCG) nelle cefalee da allergeni alimentari: trattamento cronico [Relazione in Atti di Convegno]
Martelletti, P; Bussone, G; Centonze, V; Ferrari, Anna; Frediani, F; Mangrona, D; Micieli, G; Pini, Luigi Alberto; Verri, Ap; Giacovazzo, M.
abstract

I fattori che possono scatenare un attacco di emicrania sono molteplici e vengono spesso erroneamente identificati dai pazienti come le vere cause del loro dolore. E' noto che alcune sostanze chiiche presenti in alcuni cibi possono causare cefalea. Per quanto riguarda l'emicrania si riconosce il ruolo della tiramina, e della feniletilamina. Nella terapia di profilassi dell'emicrania da allergeni alimentari il trattamento con sodiocromoglicato sembra prevenire lo scatenamento dell'attacco acuto.

1990 - Serum levels and clinical response to digoxin in congestive heart failure in the elderly [Relazione in Atti di Convegno]
Pini, Luigi Alberto; Magnavacchi, P; Ricci, S.
abstract

Since two centuries the use of digitalis glycosides for treatment of congestive heart failure has received conflicting acceptance by clinicians. We studied a group of94 old-aged patients with various degrees of chronic heat failure receiving chronically two types of digitalis(digoxin or B-metyl-digoxin) to evaluate compliance, adverse reaction and clinical picture. The study confirmed that both drugs were able to give a good compliance, with therapeutic plasma levels, without signs of accumulation. In conclusion treatment of elderly patients with low doses of digitalis without clinical signs of heart insufficiency or referring this event in the past , o showing sub-therapeutic serum digoxin levels is a practice not to be stressed

1990 - Terapia delle cefalee, comportamento alimentare e serotonina [Relazione in Atti di Convegno]
Sternieri, E; Pini, Luigi Alberto; Ferrari, Anna
abstract

Al sistema serotoninergico, anatomicamente e funzionalmente connesso con il controllo del dolore, si attribuisce un ruolo preminente nella fisiopatologia e per la terapia delle cefalee. Dopo Sicuteri che per primò rilevo nel 1961 un'aumentata escrezione urinaria di acido 5-idrossindolacetico durante l'attacco emicranico, numerose ed autorevoli sono state le osservazioni sperimentali che trovavano la serotonina coinvolta nella patogenesi dell'emicrania.

1990 - Valutazione del contenuto plasmatico e possibile uso terapeutico del glutatione in pazienti con cefalea cronica quotidiana ed uso giornaliero di associazioni analgesiche [Relazione in Atti di Convegno]
Trenti, T; Pagliani, L; Ferrari, Anna; Pini, Luigi Alberto; Sternieri, E.
abstract

La detossificazione della maggior parte dei farmaci ad azione analgesica avviene mediante coniugazione ed eliminazione attraverso la via dei mercapturati, in cui il glutatione ridotto (GSH) svolge un ruolo di primaria importanza. Allo scopo di valutare le concentrazioni plasmatiche di GSH in pazienti con abuso di analgesici è stata condotta una ricerca in pazienti con cefalea cronica quotidiana ed uso giornaliero di tali farmaci, confrontati con soggetti sani non consumatori di analgesici. Si è rilevata una significativa diminuzione delle concentrazioni di GSH plasmatico nei pazienti cefalalgici rispetto ai soggetti sani con particolare riferimento ai pazienti con sistema microsomiale indotto

1989 - Influence of antacids on the bioavailability of glibenclamide. [Articolo su rivista]
Zuccaro, P; Pacifici, R; Pichini, S; Avico, U; Federzoni, G; Pini, Luigi Alberto; Sternieri, E.
abstract

A single oral dose of glibenclamide (2.5 mg) was given to eight healthy volunteers in a randomized cross-over study after a standardized fasting and breakfast (374 kcal), with or without a concomitant intake of 10 ml of antacid suspension. Serum glibenclamide levels were determined by means of a specific radioimmunoassay method. The areas under the blood concentration-time curves (AUC0-infinity), with or without antacid, were 408.17 +/- 168.25 and 307.9 +/- 84.13 ng/ml (p less than 0.05), respectively. The peak concentrations of 96.88 +/- 49.9 and 66.19 +/- 32.35 ng/ml/h (p less than 0.05) with or without antacid, were reached in 4.13 and 3.81 h, respectively. Values of tmax, Vd and t1/2 were not affected by the presence of the antacid. A 33% increase in bioavailability of glibenclamide emerged, as seen from the respective AUC values, but no clinically remarkable effect was observed in the subjects.

1989 - Naltrexone: a post-marketing surveillance study [Abstract in Rivista]
Bergonzini, G; Ferrari, Anna; Ferretti, C; Pini, Luigi Alberto
abstract

Since 1985 we have been evaluating the side effects of chronically administered naltrexone in heroin addicts. To date the study includes 91 patients. The side-effects were the following: protracted abstinence, 41%, headache 29%, less appetite 27% of the patients.

1989 - Pharmacokinetics of tia profenic acid in headache attacks - a preliminary report [Articolo su rivista]
Pini, Luigi Alberto; Casalgrandi, L; Bertolotti, Marco; Giroldi, L.; Bergonzini, G.
abstract

This preliminary study examined the pharmacokinetics of 300 mg of tiaprofenic acid, in single oral dose, in 7 migraine patients during and out of migraine attacks. Plasma concentration of tiaprofenic acid was determined by HPLC analysis. The absorption phase did not differe between in and out migraine attacks. also other pharmacokinetic parameters evaluated were not affected by headache attacks as well. We conclude that tiaprofenic acid absorption and metabolism are not affected by migraine attacks.

1989 - Pharmacological treatment of drug dependence in daily chronic headache sufferers [Relazione in Atti di Convegno]
Sternieri, E; Pini, Luigi Alberto; Bergonzini, G; Giroldi, L; Ferrari, Anna
abstract

Today, treatment with drugs is the principal therapeutic defence against the different forms of primary headache. However, whilst there are many drugs of proven efficacy available for the prophylaxis of episodic headaches, treatment is much more difficult of those patients who arrive at headache centres complaining of a headache which over the yars has bevome daily and for which they have also been taking analgesic mixture every day for years without any improvement; indeed the pain has rather got worse.

1989 - Pharmacological treatment of drug dependence patients suffering from daily chronic headache [Abstract in Rivista]
Sternieri, E; Bergonzini, G; Ferrari, Anna; Giroldi, L; Pini, Luigi Alberto
abstract

Daily use of analgesic drugs, even if ineffectiv, is common in daily chronic headache. Generally this is considered abuse. The main problem is use of barbiturates.

1989 - Prophylaxis of food-induced migraine with cromolyn sodium: efficacy of short and long-term use [Relazione in Atti di Convegno]
Martelletti, P; Bussone, G; Centone, V; Ferrari, Anna; Frediani, F; Magrone, D; Micieli, G; Pini, Luigi Alberto; Verri, Ap; Giacovazzo, M.
abstract

Some food contain a wide variety of allergenic determinants that are able to provoke headache by release of neurovasoactive substances. Prophylact treatment with cromolyn sodium may chance the incidence of migraine attacks induced by provoking foods.

1988 - Chronic treatment with naltrexone and hepatic functions in heroin addicts [Articolo su rivista]
Pini, Luigi Alberto; Ferrari, Anna; Giroldi, G; Bergonzini, G; Sternieri, E.
abstract

This study evaluated the influence of long term naltrexone treatment on hepatic function in 14 heroin addicts.

1988 - INFLUENCE OF PROLONGED THERAPY WITH FLUNARIZINE ON GLUCOSE, INSULIN AND C-PEPTIDE METABOLISM [Articolo su rivista]
Pini, Luigi Alberto; Ferrari, Anna; E., Sternieri
abstract

The use of flunarizine in the preventive treatment of headaches and migraine is now widely done. Taking into account that the main and more frequent side effects of this treatment are weight gain and increase of appetite, with a typical carbohydrates craving, we studied the influence of a prolonged treatment of flunarizine on glucose, C- peptide and insulin metabolism in headache sufferers. All these substances were studied before and after treatment and we did not find significant differences after the treatment. So we could conclude that this drug even if increases appetite , does not interfere with glucose metabolism and it is possible to hypothesize that the carbohydrate craving could be related to a facilitate income of glucose into the cell.

1988 - Naltrexone: basi farmacologiche ed impiego clinico nella prevenzione delle recidive della tossicodipendenza da eroina [Articolo su rivista]
Bergonzini, G; Ferrari, Anna; Giroldi, L; Pini, Luigi Alberto
abstract

Il naltrexone è utilizzato soprattutto come farmaco aggiuntivo nella terapia integrata di riabilitazione psicosociale per il recupero dei dipendenti da morfinici. Un protocollo prevede la somministrazione giornaliera di 50 mg/os ma il Naltrexone può essere somministrato anche con altri protocolli. In un trattamento di mantenimento quello più utilizzato è il seguente: 1) Verificare preliminarmente con accertamenti urinari che il paziente è rimasto drug-free; questo stato dovrebbe essere verificato anche con il test al Narcan (Naloxone 0,4-0,8 mg i.v. o 0,8 mg sotto cute) 2) iniziare il trattamento aumentando progressivamente e lentamente la dose: questa fase viene di norma definita “induzione al naltrexone”. Un protocollo prevede di iniziare l’induzione al naltrexone con 10 mg il 1° giorno, 20 mg il 2° giorno, 30 mg il 3° giorno, 40 mg il 4° giorno e 50 mg il 5° giorno. Secondo altri autori il raggiungimento della dose di 50 mg in 5 giorni comporta un aumento dei “drop-outs” dovuto al fatto che i pazienti verificano se effettivamente l’effetto dell’eroina è bloccato fin dalla fase iniziale del trattamento, cioè quando la dose non è ancora sufficiente a produrre un blocco totale della durata di 24 ore. Questi autori consigliano quindi di iniziare il trattamento con 25 mg/os e, se non compaiono entro 1-2 ore segni di astinenza, di aumentare la dose fino a 50 mg nella stessa giornata. 3) Il trattamento può quindi proseguire con 50 mg/die/os o con 100 mg il Lunedì, 100 mg il Mercoledì e 150 mg il Venerdì/os/settimana e proseguire per mesi.

1988 - PHARMACOKINETICS OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS [Relazione in Atti di Convegno]
E., Sternieri; Pini, Luigi Alberto
abstract

Pharmacokinetics of NSAIDS is relevant both for therapeutic and side effects especially with regard in "A" type of side effects and in their incidence. It is observed that NSAIDs reach high concentrations in body compartments in which cause therapeutic or unwanted effects, and therefore it is important to know pharmacokinetics of these drugs. The four phases of pharmacokinetics are explained, and the differences within different drugs are reported. It is important to note that from there differences it should be possible avoid known side effects or minimize it by using an appropriate drug dispensation regimen. Finally the investigation of these pharmacokinetic parameters could lead to develop better drugs as well to avoid accidents with new compounds extensively employed in clinical practice.

1988 - Terapie farmacologiche in atto: rischio da interazioni in corso di anestesia. [Articolo su rivista]
Morselli, L; Piccinini, P; Pini, Luigi Alberto; Bozzola, M; Stacca, R.
abstract

Le interazioni farmacologiche sono un evento molto frequente nella pratica clinica, ed altrettatnto freqeuntemente sono sottovalutate e sotto diagnosticate. Infatti la percentuale delle interazioni farmacoloiche aumenta con l'aumentare del numero di farmaci somministrati e questo si verifica costantemente con l'aumentare dell'età. Appare quindi necessario approntare procedure anestesiologiche che prendano in considerazione la possibilità di interazione con i farmaci anestetici dei farmaci assunti precedemntemente dai pazienti. Quindi è necessario avere a disposizione strumenti di facile consultazione che possano metetre sull'avviso su possibili inetrazioni potenzialemnte preicolose o clinicamente rilevanti tar i farmaci assunti o prescritti in altro luogo e i farmaci necessario in corso di anestesia.

1987 - Analgesic abuse in chronic headache sufferers [Abstract in Rivista]
Ferrari, Anna; E., Sternieri; G., Bergonzini; L., Giroldi; Pini, Luigi Alberto
abstract

In the last year we began to study analgesic abuse in chronic headache sufferers in order to evaluate possible organic or psycho-social damages. We submitted a questionnaire to 50 patients who referred an "abuse" of more than 30 tablets or 15 suppositories at month. From the data we concluded that this abuse is a relevant social problem because determines a "reinforcement of distressing behaviour of headache sufferers people" that takes to chronicity of the headaches.

1987 - L'indagine ENG nello studio delle cefalee primarie [Articolo su rivista]
G., Guidetti; L., Barbieri; A., Ferarri; Pini, Luigi Alberto
abstract

E' stato effettuato uno studio su 165 casi di cefalea e sono stati studiati vari parametri dell'ENG. In particolare durante la crisi è stato studiata la Velocità Massima di Fase Lenta (VAFL) che è risulatta alterata nel 75% dei casi. In base a questi risultati sembra emergere che gli emicranici sono caratterizzati da una riduzione della funzione dei centri vetsibulo-oculo-motori nel periodo intercritico e da un notevole aumento della risposta nistagmica prevalentemente omolaterale al dolore, associato ad una alterazione del riflesso otticocinetico, del pursuit e dell'IFO, come si fosse presente un difetto della capacità di modulazione centrale.

1987 - La flunarizina nella profilassi delel crisi emicraniche delle cefalee cclassiche e comuni [Articolo su rivista]
Pini, Luigi Alberto; Ferrari, Anna; G., Bergonzini; E., Sternieri
abstract

Sono stati trattati con flunarizina come profilassi dell'emicrania 74 pazienti con emicrania comune o classica alla dose di 5 mg alla sera per 3 mesi. Il 75% dei pazienti senza differenze tra emicrania comune e classica ha avuto un miglioramento significativo della frequenza degli attacchi rispetto al periodo precedente. Gli effetti collaterali principali sono stati l'aumento di appetito e di peso.

1987 - Per un "rationale" di un centro cefalee. L'esperienza del Centro per lo Studio delle Cefalee dell'Universita degli Studi di Modena. [Articolo su rivista]
Pini, Luigi Alberto
abstract

L'autore prende in considerazione le caratteritiche necessarie per la organizzazione di un Centro cefalee in base alle indicazioni della organizzazione sanitaria e alla potenzialità diagnsotiche e terapeutiche delle varie strutture

1986 - EFFECTIVENESS OF FLUNARIZINE IN ALTERING ELECTRONYSTAGMOGRAPHIC PATTERNS IN MIGRAINE PATIENTS - A PRELIMINARY-REPORT [Articolo su rivista]
Pini, Luigi Alberto; Ferrari, Anna; Guidetti, G; Galetti, G; Barbieri, L; Sternieri, E.
abstract

In this double-blind study versus placebo, the anti-migraine efficacy of flunarizine 20 mg/per os/day for 14 days, followed by 10 mg/per os/day up to 120 days has been evaluated in 30 patients suffering from common and classical migraine. During the trial the vestibular function (slow phase velocity (SPV) and number of spikes) was also studied. To date 18 patients have completed the study. The results show a significant difference before and after the treatment with flunarizine, while no difference was observed in the placebo group, with regard to headache unit indices. Flunarizine seems to increase SPV max, which is reduced between attacks in migraine patients; the number of spikes does not change significantly.

1986 - Influence of chronic therapy with flunarizine on glucose, insulin and C-peptide metabolism [Abstract in Rivista]
Pini, Luigi Alberto; Ferrari, Anna; Massari, M.; Montanari, P.; Luciani, A.; Sternieri, E. .
abstract

The aim of the study was to evaluate the effetct of flunarizine on glucose insulin and c-peptide metabolism in migraneurs, because the increase of appitite and weight gain are the most frequent side effect of this treatment. In cocnlusion the chonic treatment with flunarizine improved the glucose tolerance, while C-peptide and insulin secretion were unchanged. The data suggest that flunarizine could incerase the peripheral glucose intake.

1986 - Phenytoin-Treatment Of Rdeb Vegetans [Articolo su rivista]
Pini, Luigi Alberto; G., Girolomoni; Coppini, Maurizio; Pincelli, Carlo
abstract

To assess the potential short- and long-term efficacy of phenytoin in treating recessive dystrophic epidermolysis bullosa (RDEB), we treated a patiens with therapeutic doses of oral phenytoin (blood level, 8 to 10 micrograms/mL) for an 10 moths period During this tretament we recorded a percentage decrease in blistering of the skin over 50% This report suggest that phenytoin seems to have therapeutic efficacy in RDEB.

1986 - The electronystagmographic examination in the study of migraine [Articolo su rivista]
Guidetti, G; Barbieri, L; Ferrari, Anna; Pini, Luigi Alberto
abstract

The association of dizziness and headache is quite frequent and it has been known for a long time. The visual and auditory evoked potentials and EEG had already shown a damage of CNS in migrainous. The vestibular tests with ENG, which is enclosed in the routine study of the patients of the Headache Centre of Modena University (Italy), has shown a high percentage of alterations in different tests. Out of crisis a decrease of VOR and troubles of OKN and pursuit are noted. During crisis the reflectivity increases above all in the same part of the pain and a further alteration of smooth pursuit is observed. The Nomiphensine test suggest that these alterations of CNS are caused by changes in biochemistry of CNS, above all in the monoamines.

1985 - ENG patterns in migraine [Capitolo/Saggio]
Pini, Luigi Alberto; G., Guidetti; Ferrari, Anna; G., Bergamini; E., Sterneiri; G., Galetti
abstract

We have previously described a number of oto- neurological abnormalities in patients with dizziness and headache even without organic changes on the central nervous system. In order to validate these data, we have added to the number of cases nd have introduced a new ENG test, the pursuit test, to study the activity of oculomotor centers. Again we evaluated the influence of cervical arthrosis on pathgenesis of migraine by cervical nystagmous test. Finally we used a beta-blocker and a calcium- anatgonist to record the influence of these drugs on ENG parameters.

1985 - INFLUENCE OF FLUNARIZINE ON THE ALTERED ELECTRONYSTAGMOGRAPHIC (ENG) RECORDINGS IN MIGRAINE [Articolo su rivista]
Pini, Luigi Alberto; Ferrari, Anna; Guidetti, G.; Galetti, G; E., Sternieri
abstract

Flunarizine, a slow-channel calcium blocker, appeared to be effective in the prophylactic treatment of common and classic migraine in 29 out-patients included in a double-blind clinical trial. After a two-month placebo period, half the patients were treated with flunarizine, 10 mg a day for up to 120 days, half with placebo. Electronystagmographic (ENG) recordings were performed at the end of the common placebo period and after two and four months of treatment, respectively. There was a significant reduction in Headache Unit Index (HUI) and Headache Unit Index Corrected (HUIC) (42% and 40.5% respectively) in the flunarizine-treated group but not in the placebo group. Analgesic intake was reduced and intensity of pain was unchanged in both groups throughout the trial. ENG data were not significantly affected by flunarizine treatment.

1984 - Dizziness and headache [Articolo su rivista]
Guidetti, G; Bergamini, G; Pini, Luigi Alberto; Galetti, G; Sternieri, E.
abstract

Dizziness and headache have been known to be associated in both adults and children, since early this century. Otoneurological examination of headache sufferers at the University of Modena Headache Centre revealed a high percentage of ENG alterations indicating a mainly bulbo-pontine vestibular disorder. The lesion, which is more significant on the side more affected, is modified during attacks and with time. The authors suggest that in these patients migraine and dizziness have a common pathogenesis in alterations of neuromediators and/or their receptors and that ENG may be useful in evaluating headache.

1983 - Ambiti e limiti delle prescrizioni farmaceutiche nell'esercizio dell'odontoiatria e protesi dentaria [Articolo su rivista]
E., Sternieri; G., Beduschi; E., Mincione; Pini, Luigi Alberto; P., Pecchi
abstract

L'articolo esamine le problematiche legate alla introduzione della nuova laurea in Odontoiatria e Protesi dentaria in relazione alla possibilità di prescfrizione dei farmaci da parte dei nuovi laureati. In conclusione l'articolo propone di formulare un prontuario ad ho per questi laureati che però non abbia valore vincolante.

1983 - Circadian variations of proopiocortin-related peptides in children with migraine. [Articolo su rivista]
Facchinetti, Fabio; G., D'Attoma; F., Petraglia; Pini, Luigi Alberto; E., Sternieri; A. R., Genazzani
abstract

Basal and throughout-the-day variations of B-lipotropin (BLPH), B-endorphin (BEP), ACTH and cortisol plasma levels were studied in seven prepubertal children who had been affected by common migraine for periods of 6-26 months and in six healthy volunteers. Despite normal cortisol concentrations, children with migraine show higher BLPH (15.1 +/- 2.7 fmol/ml, M +/- SE), ACTH (25 +/- 2.7) and BEP (9.1 +/- 1.1) levels than controls. In both groups of children, evening values (8 p.m.) were significantly lower than morning values, but in migraineurs the decrease of the three peptides was less. The raised proopiocortin-related peptide plasma levels found in children suffering from migraine cannot be explained at present, although the discomfort experienced by the patients may create a situation of chronic stress which could explain such a finding. Whatever the explanation is, these findings differentiate prepubertal migraine from the most severe forms of headache occurring in adult life where lower than normal opioid levels have been demonstrated.

1983 - Drug addiction during pregnancy. [Articolo su rivista]
Volpe, Annibale; E., Correnti; A., Grasso; G. C., Di; Pini, Luigi Alberto; E., Sternieri
abstract

On the basis of current literature and their own experience, the authors discuss (1) the major complications possible in pregnant drug addicts, (2) whether the complications can be attributed to deficient prenatal care or to effects of drug abuse, and (3) the best prenatal care of drug-addicted mothers.

1982 - La sofferenza dell'apparato vestibolare nel paziente cefalalgico. Considerazioni a proposito di osservazioni ENG in 53 casi [Articolo su rivista]
G., Galetti; G., Guidetti; G., Bergamini; Pini, Luigi Alberto; M., Botti
abstract

Ci sono significative relazioni tra vertigini e cefalea e sono state riportate in letteratura negli ultimi anni. Abbiamo studiato una serie di pazienti che afferivano al Centro cefalee dekll'Università di Modena che sono stati sottoposti a un esame audiometrico e otoneurologico. E' stat registrata una frequente lieve-moderata perdita della acutezza uditiva. Sono state registarte anomalie cemtarli all'esame ENG nel 95% dei acsi. Mentre le anomalie qualitative erano bilaterali, quelle quantitative sono correlate al lato più colpito dalla cefalea. In base a questi reperti si postula l'ipotesi che vertigini e cefalea presentini aspetti patogenetici comuni.