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Most nucleoside kinases, besides the catalytic domain, feature an allosteric domain which modulates their activity. Generally, non-substrate analogs, interacting with allosteric sites, represent a major opportunity for developing more selective and safer therapeutics. We recently developed a series of non-nucleoside non-competitive inhibitors of human adenosine kinase (hAK), based on a pyrrolobenzoxa(thia)zepinone scaffold. Based on computational analysis, we hypothesized the existence of a novel allosteric site on hAK, topographically distinct from the catalytic site. In this study, we have adopted a multidisciplinary approach including molecular modeling, biochemical studies, and site-directed mutagenesis to validate our hypothesis. Based on a three-dimensional model of interaction between hAK and our molecules, we designed, cloned, and expressed specific, single and double point mutants of hAK (Q74A, Q78A, H107A, K341A, F338A, and Q74A-F338A). Kinetic characterization of recombinant enzymes indicated that these mutations did not affect enzyme functioning; conversely, mutated enzymes are endowed of reduced susceptibility to our non-nucleoside inhibitors, while maintaining comparable affinity for nucleoside inhibitors to the wild-type enzyme. This study represents the first characterization and validation of a novel allosteric site in hAK and may pave the way to the development of novel selective and potent non-nucleoside inhibitors of hAK endowed with therapeutic potential., (© 2015 John Wiley & Sons A/S.)

Background: Because guanine-based herpes simplex virus thymidine kinase inhibitors are not orally available, we synthesized various 6-deoxy prodrugs of these compounds and evaluated them with regard to solubility in water, oral bioavailability, and efficacy to prevent herpes simplex virus-1 reactivation from latency in a mouse model., Methods: Organic synthesis was used to prepare compounds, High Performance Liquid Chromatography (HPLC) to analyze hydrolytic conversion, Mass Spectrometry (MS) to measure oral bioavailability, and mouse latent infection and induced reactivation to evaluate the efficacy of a specific prodrug., Results: Aqueous solubilities of prodrugs were improved, oxidation of prodrugs by animal cytosols occurred in vitro, and oral absorption of the optimal prodrug sacrovir™ (6-deoxy-mCF3PG) in the presence of the aqueous adjuvant Soluplus® and conversion to active compound N(2)-[3-(trifluoromethyl)pheny])guanine (mCF3PG) were accomplished in mice. Treatment of herpes simplex virus-1 latent mice with sacrovir™ in 1% Soluplus in drinking water significantly suppressed herpes simplex virus-1 reactivation and viral genomic replication., Conclusions: Ad libitum oral delivery of sacrovir™ was effective in suppressing herpes simplex virus-1 reactivation in ocularly infected latent mice as measured by the numbers of mice shedding infectious virus at the ocular surface, numbers of trigeminal ganglia positive for infectious virus, number of corneas that had detectable infectious virus, and herpes simplex virus-1 genome copy numbers in trigeminal ganglia following reactivation. These results demonstrate the statistically significant effect of the prodrug on suppressing herpes simplex virus-1 reactivation in vivo., (© The Author(s) 2015.)

Background: The treatment of migraine attacks with aura by triptans is difficult since triptans most probably are not efficacious when taken during the aura phase. Moreover, there are insufficient data from randomised studies whether triptans are efficacious in migraine attacks with aura when taken during the headache phase. In this metaanalysis, we aimed to compare the efficacy of frovatriptan versus rizatriptan, zolmitriptan, and almotriptan., Methods: Five double-blind, randomized, controlled crossover trials were pooled. All trials had an identical design. Patients were asked to treat three consecutive migraine attacks with frovatriptan 2.5 mg and three consecutive migraine attacks with a comparative triptan (rizatriptan 10 mg; zomitriptan 2.5 mg; almotriptan 12.5 mg)., Results: In this analysis, 117 migraine attacks with aura could be included (intention-to-treat population). The mean headache intensity after 2 hours was 1.2 +/- 1.0 for frovatriptan and 1.6 +/- 1.0 for the other triptans (p<0.05); all triptans showed significant improvement of headache. Frovatriptan resulted in significantly lower relapse rates at 24 hours and 48 hours when taken in migraine attacks with aura., Conclusions: Our data suggest that frovatriptan is efficacious and even superior in some endpoints also when taken during the headache phase in migraine attacks with aura. This is of particular importance for those many patients who have migraine attacks both without and with aura.

Objectives: To evaluate the prevalence of KCNK18 gene mutations in a dataset of Italian migraineurs, with and without aura, and in healthy controls, and to investigate in silico the functional effects of the mutations., Background: A role for the KCNK18 gene encoding for TRESK, a member of the family of potassium channel, has been recently suggested in migraine with aura., Methods: We sequenced the KCNK18 gene in 425 migraineurs (255 with aura and 170 without aura) and 247 healthy controls., Results: Five genetic variants (R10G, C110R, Y163Y, S231P, and F372L) were found in 13 (5.1%) out of 255 migraine with aura patients, and 6 variants (R10G, D46D, C110R, Y163Y, S178T, and S231P) were identified in 12 (7.1%) out of 170 migraine without aura patients. In 2.8% of controls, the R10G and L20V substitutions were found. In silico analysis suggested that C110R, S178T, S231P, and F372L mutations may have potential damaging effect on channel function, whereas the remaining mutations may have low damaging effect., Conclusions: Our study shows the presence of several KCNK18 gene mutations in both migraine with aura and migraine without aura. However, the precise role of this gene in migraine predisposition deserves further studies., (© 2014 American Headache Society.)

Background: The present pharmacoeconomic study compared the direct and indirect costs of using frovatriptan versus rizatriptan in the acute treatment of migraine., Methods: Data on the cost-efficacy of the two triptans were derived from a recently published Italian, multicenter, randomized, double-blind, cross-over patient preference study, comparing frovatriptan versus rizatriptan. The direct costs were obtained by calculating the drug consumption, both of triptans and rescue medications. Prices of currently marketed drugs were obtained from Italian Drug Agency price list. The indirect costs were those related to absenteeism from the workplace due to migraine., Results: 129 of the 148 patients with a current history of migraine randomized to the two study drugs and completing the study were analyzed. The number of attacks treated with only 1 dose of study drug was higher with frovatriptan (157 vs. 147), whereas the number of attacks treated with ≥2 doses of study medication was higher with rizatriptan (122 vs. 110 and 74 vs. 67, respectively). However, more patients treated with frovatriptan took a rescue medication (71 vs. 59). The total direct cost per attack (including study drug rescue medication) was 9.12 € for frovatriptan and 13.54 € for rizatriptan (p < 0.05 between-treatments). As for indirect costs, in the group of patients treated with frovatriptan the mean number of lost working hours was significantly (p < 0.05) lower (1.5 h) compared to the subjects who used rizatriptan (2.8 h). Based on the earned income per unit of work, indirect costs per attack resulted to be 24.55 € for frovatriptan and 45.84 € for rizatriptan. Overall, the total costs, including direct and indirect costs, were evaluated to be 33.67 € for frovatriptan and 59.38 € for rizatriptan, respectively., Conclusions: Within the limitations of this model analysis, frovatriptan was found to be significantly more cost-effective than rizatriptan. This outcome can be explained by the lower acquisition cost of frovatriptan, the need for fewer doses, and the loss of fewer working hours. This finding could drive selection of the most appropriate oral treatment for acute migraine attacks based on both individual patient's needs and the cost-effectiveness of the available drugs., Trial Registration: 2006-002572-17 (EudraCT).

The interest that surrounds the bacterium Helicobacter pylori (H. pylori) is due not only to its causal role in several gastroduodenal diseases, but also to its supposed involvement in the pathogenesis of extra-gastric manifestations. This review provides a literature update on the hypothetic correlation between H. pylori and headache. To identify all publications on this issue, a MEDLINE search of all studies published in English from 1965 to 2013 was conducted. The authors examined three aspects of this potential association: epidemiology, intervention trials and pathogenesis. While in the former, the results are contradictory, in the intervention studies, it has been documented that at 6 and 12 months, bacterial eradication is associated to disappearance of symptoms in 23% and 28% of cases, and to a significant decrease of intensity, frequency and duration of acute attacks in the remaining patients. Under a pathogenetic aspect, if H. pylori has a role, it does not act through oxidative stress. In conclusion, the eradication of H. pylori seems efficient at least in a subgroup of patients suffering from migraine. Further investigations should focalize on particular subgroups of patients and, encouraged from data produced by intervention studies, evaluate the long-term benefit of eradication.

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.

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.

Herpes simplex virus (HSV) types 1 and 2 thymidine kinases (TK) are responsible for phosphorylation of antiherpes acyclonucleosides such as acyclovir (ACV) and 9-(4-hydroxybutyl)guanine (HBG). Related compounds, the N 2 -phenyl-9-(hydroxyalkyl)guanines, are devoid of direct antiviral activity, but potently inhibit the viral TKs and block viral reactivation from latency in vivo . The similarity in structure between the acyclonucleosides and TK inhibitors raised the question of the relevance of phosphorylation of certain of the latter analogs in their mechanisms of action. Using recombinant TKs and HPLC analysis of reaction mixtures, we report that the lead TK inhibitor N 2 -phenyl-9 -(4-hydroxybutyl)guanine (HBPG) and its pentyl homolog (HPnPG) are excellent substrates for the enzymes, approaching the efficiency with which the natural substrate thymidine is phosphorylated, and significantly better than ACV or HBG. Other 9-hydroxyalkyl congeners are substrates for the enzymes, but with much poorer efficiency. HBPG triphosphate was a poor inhibitor of HSV DNA polymerase, the target of acyclonucleoside triphosphates, suggesting that phosphorylation of HBPG is not important in its mechanism of blocking viral reactivation in vivo . The fact that HBPG is an efficient substrate is consistent, however, with its binding mode based both on molecular modeling studies and x-ray structure of the HBPG:TK complex.

The objectives of this study are to assess the efficacy and safety of frovatriptan, and rizatriptan in the subgroup of women with menstrually related migraine of a multicenter, randomized, double blind, cross-over study. Each patient received frovatriptan 2.5 mg or rizatriptan 10 mg in a randomized sequence: after treating 3 episodes of migraine in not more than 3 months with the first treatment, the patient had to switch to the other treatment. Menstrually related migraine was defined according to the criteria listed in the Appendix of the last IHS Classification of Headache disorders. 99 out of the 125 patients included in the intention-to-treat analysis of the main study were of a female gender: 93 had regular menstrual cycles and were, thus, included in this analysis. A total of 49 attacks classified as menstrually related migraine were treated with frovatriptan and 59 with rizatriptan. Rate of pain relief at 2 h was 58% for frovatriptan and 64% for rizatriptan (p = NS), while rate of pain free at 2 h was 31 and 34% (p = NS), respectively. At 24 h, 67 and 81% of frovatriptan-treated, and 61 and 74% of rizatriptan-treated patients were pain free and had pain relief, respectively (p = NS). Recurrence at 24 h was significantly (p < 0.01) lower with frovatriptan (10 vs. 32% rizatriptan). Frovatriptan was as effective as rizatriptan in the immediate treatment of menstrually related migraine attacks while showing a favorable sustained effect with a lower rate of migraine recurrence. These results need to be confirmed by randomized, double-blind, prospective, large clinical trials.

Based on the finding that aerobic Gram-positive antibacterials that inhibit DNA polymerase IIIC (pol IIIC) were potent inhibitors of the growth of anaerobic Clostridium difficile (CD) strains, we chose to clone and express the gene for pol IIIC from this organism. The properties of the recombinant enzyme are similar to those of related pol IIICs from Gram-positive aerobes, e.g. B. subtilis. Inhibitors of the CD enzyme also inhibited B. subtilis pol IIIC, and were competitive with respect to the cognate substrate 2'-deoxyguanosine 5'-triphosphate (dGTP). Significantly, several of these inhibitors of the CD pol IIIC had potent activity against the growth of CD clinical isolates in culture.

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.

Background: The cardiac left ventricle responds to pressure overloads with mechanisms culminating in irreversible structural/functional cardiac alterations (left ventricular hypertrophy and/or diastolic dysfunction), inducing myocardial cells to secrete natriuretic peptides (NT-proBNP) antagonists of the renin-angiotensin-aldosterone system. The aim of this study was to evaluate the diagnostic accuracy of serum NT-proBNP levels in order to detect structural/functional cardiac diseases assessed by echocardiography., Methods: A total of 126 consecutive newly diagnosed, never before treated, hypertensive patients (30-67 years) were enrolled, and clinical, echocardiography parameters and biochemical data were collected. Our reference was the presence of structural/functional cardiac disease (CSFD) and our index text was the serum NT-proBNP levels., Results: NT-proBNP levels in CSFD patients were ~2 times higher than in non-CSFD subjects (median 61 vs 29 ng/L, n=50 and 76, respectively); in addition, 60% of CSFD subjects (only 14% of which with pathological levels, >125 ng/L), and 30% without CSFD showed NT-proBNP concentrations higher than 50 ng/L. However, ROC curves demonstrated a low specificity (38%) (calculated at 90% sensitivity at a cut-off of 22.5 ng/L)., Discussion: NT-proBNP levels, as a screening tool for cardiac structural/functional disease, appear to be limited, because of the low specificity. However, the strong association between its concentration and the establishment of irreversible cardiac hypertrophy prompts successive studies aimed to ascertain the use of its serum levels as an early alert indicator of disease severity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The objective of this study was to assess patient satisfaction with acute treatment of migraine with frovatriptan or rizatriptan by preference questionnaire. 148 subjects with a history of migraine with or without aura (IHS 2004 criteria), with at least one migraine attack per month in the preceding 6 months, were enrolled and randomized to frovatriptan 2.5 mg or rizatriptan 10 mg treating 1-3 attacks. The study had a multicenter, randomized, double-blind, cross-over design, with treatment periods lasting <3 months. At the end of the study, 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 h, and recurrent and sustained pain-free episodes within 48 h. 104 of the 125 patients (83%, intention-to-treat population) expressed a preference for a triptan. The average preference score was not significantly different between frovatriptan (2.9±1.3) and rizatriptan (3.2±1.1). The rates of pain-free (33% frovatriptan vs. 39% rizatriptan) and pain relief (55 vs. 62%) episodes at 2 h were not significantly different between the two treatments. The rate of recurrent episodes was significantly (p<0.001) lower under frovatriptan (21 vs. 43% rizatriptan). No significant differences were observed in sustained pain-free episodes (26% frovatriptan vs. 22% rizatriptan). The number of patients with adverse events was not significantly different between rizatriptan (34) and frovatriptan (25, p=NS). The results suggest that frovatriptan has a similar efficacy to rizatriptan, but a more prolonged duration of action., (© Springer-Verlag 2010)

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 < 0.05), but not significantly different from each other. In conclusion, PCF was well-tolerated and effective in the treatment of acute TTH.

Studies in experimental animals have suggested that the hypocretin/orexin system may be involved in migraine pathophysiology. Using a case-control design study, we genotyped 246 migraine patients and 239 healthy controls for the 1246G-->A polymorphism of the hypocretin receptor 2 (HCRTR2) gene. Genotypic and allelic frequencies of the examined polymorphism were similarly distributed between cases and controls (chi2 = 2.22, P = 0.14 and chi2 = 2.45, P = 0.29, respectively). When different migraine subgroups were compared (migraine with aura vs. migraine without aura and episodic vs. chronic migraine) no significant difference was found. Comparison of the clinical features of the disease with the 1246G-->A genotypes showed no significant difference. Our data suggest that the HCRTR2 gene is not a genetic risk factor in migraine.

The interest that surrounds the bacterium Helicobacter pylori (H. pylori) is due not only to its causal role in several gastroduodenal diseases, but also to its supposed involvement in the pathogenesis of extragastric manifestations. This review provides a literature update on the hypothetic correlation between H. pylori and headache. The authors examine three aspects of this potential association: epidemiology, intervention trials and pathogenesis. Regarding the first, apart in some subgroups, no difference in prevalence exists between patients and controls. Considering the intervention studies, it is documented that, at 6 and 12 months, bacterial eradication is associated to disappearance of symptoms in 23% and 28% of cases, and to a significant decrease of intensity, frequency and duration of acute attacks in the remaining patients. As to the pathogenetic aspect, if H. pylori has a role, it does not act through oxidative stress. In conclusion, the involvement of H. pylori infection in the pathogenesis of headache is unclear. Further investigations should focalize on particular subgroups of patients and, encouraged from data produced by intervention studies, evaluate the long-term benefit of eradication.

New genetic evidence strongly supports a role for the immune system in the pathogenesis of essential hypertension (EH) through chemokines and their receptors (CCR) involvement. The aim of the present study was to evaluate the possible relation between CCR2 and CCR5 alleles and blood pressure (BP) levels in hypertensive subjects. In all, 118 essential hypertensive outpatients (male 90, female 28; stage I and II; age 27-54 years; not previously treated with antihypertensive drugs) were selected for the study. All of the subjects underwent office BP measurement. Subsequently, 24-h ambulatory BP monitoring (ABPM) was performed with a Spacelabs 90207 monitor during a regular working day. CCR264I and CCR5Delta32 polymorphisms were determined by polymerase chain reaction (PCR), following the standard molecular biology protocols. Allelic frequencies were the following: CCR5Delta32= 0.097, CCR264I=0.101. Logistic regression analysis showed an association between the CCR5Delta32 allele and the following: 24-h systolic BP (SBP >140 mmHg; p = 0.027), values over the 50th percentile of 24-h SBP (p = 0.032), and the values over the 50th percentile of nighttime SBP (p = 0.039). Office BP showed an association with the Delta32 allele in a range over the 75th percentile of SBP (p = 0.087) and the 75th percentile of DBP (p = 0.085). No significant association was observed for CCR264I and BP levels or between physiological nocturnal BP decline and genotype. The observed results not only support the role of the immune system in the development and maintenance of hypertension, but they also indicate an influence of CCR5Delta32 polymorphism on the establishment of BP levels.

We examined the distribution of HLA-DRB1 alleles in a cohort 255 Italian migraine patients and in a control group of 325 healthy subjects. 214 patients fulfilled the ICHD-II criteria for migraine without aura and 41 patients the criteria for migraine with aura. The frequency of DRB1*16 allele was found to be significantly increased in migraine without aura patients (p=0.02; OR 1.97, 95% CI: 1.10-3.54) than in healthy controls. The frequencies of HLA-DRB1 alleles were not significantly different between migraine with aura patients and controls. We did not detect any effect of DRB1 alleles on age at onset, duration of the disease, frequency and duration of migraine attacks. Our data suggest the presence of a genetic susceptibility factor for migraine without aura within the HLA region.

Recent studies suggested that genetic factors play a role in cluster headache (CH). However, the type and the number of genes involved in the disease are still unclear. We performed an association study in a cohort of Italian CH patients to evaluate whether a particular allele or genotype of the Clock gene would modify the occurrence and the clinical features of the disease. One hundred and seven CH patients, diagnosed according to the International Classification of Headache Disorders, 2nd Edition, (ICHD-II) criteria, and 210 healthy age, sex and ethnicity-matched controls were genotyped for the 3092 T-->C Clock gene polymorphism (also known as 3111 T-->C). Phenotype and allele frequencies were similarly distributed in CH patients and controls. The clinical features of the disease were not significantly influenced by different genotypes. In conclusion, our study suggests that the 3092 T-->C polymorphism of the Clock gene is unlikely to play an important role in cluster headache.

Objective: To evaluate whether polymorphisms of the HFE gene would modify the occurrence and the clinical features of cluster headache (CH)., Background: Recent studies suggested that iron metabolism may be involved in the pathophysiology of primary headaches. The HFE gene encodes for a protein that modulates iron absorption. Mutations in this gene are responsible for toxic iron overload in several body organs., Methods: Genomic DNA was extracted from 109 CH patients and 211 age and sex-matched healthy controls and genotyped for the C282Y and H63D mutations of the HFE gene. Allele and genotype frequencies of the HFE gene were compared between cases and controls. The clinical characteristics of the disease were compared according to the different HFE gene genotypes., Results: No C282Y mutation was found in both cases and controls. The prevalence of the H63D mutation was nearly identical in cases and controls. The four patients carrying the HFE D63D genotype showed a significantly (P < .001) later age at onset of the disease in comparison with both H63H and H63D patients. The remaining clinical characteristics of the disease did not significantly differ in the presence or absence of the H63D mutation., Conclusion: Our data do not support the hypothesis that genetic variations within the HFE gene are associated with CH. However, the HFE gene may influence the disease phenotype and may be regarded as a disease modifier gene.

The antiviral activity of six medicinal plants from Brazilian Atlantic Tropical Forest was investigated against two viruses: herpes simplex virus type 1 (HSV-1) and poliovirus type 2 (PV-2). Cuphea carthagenensis and Tillandsia usneoides extracts showed the best antiherpes activity. T. usneoides dichloromethane, ethyl acetate and n-butanol extracts, and Lippia alba n-butanol extract showed inhibition of HSV-1, strain 29R/acyclovir resistant. In addition, only L. alba ethyl acetate extract showed antipoliovirus activity. These results corroborate that medicinal plants can be a rich source of potential antiviral compounds.

Hypertensive crises are commonly observed in an emergency room. Regardless blood pressure values, hypertensive crises are classified in emergencies, characterized by life-threatening acute organ damage, and urgencies, with no evidence of acute or progressive organ injury. In an hypertensive emergency an appropriate and immediate management with parenteral drugs is mandatory, while in an hypertensive urgency blood pressure should be decreased within 24-48 h with orally active agents. This article reviews the spectrum of clinical syndromes that comprise hypertensive emergencies, focusing on specific drugs and therapeutic strategies available in the emergency department, based on current literature. Since no randomized prospective trials are available, an evidence-based approach recommending an optimal therapeutical management is not possible. Much of the therapy is therefore entirely empirical and based on the underlying pathophysiologic and clinical findings. Further studies are needed to clarify pathophysiologic mechanisms in order to optimize therapeutic approach.

Background: Arterial hypertension is a risk factor for atherosclerosis of whose pathogenesis is unknown. Growing evidence underscores the causative role of endothelial dysfunction. A possible association between Helicobacter pylori infection and cardiovascular and autoimmune disorders has been found. The release of cytotoxic substances either of bacterial origin or produced by the host may represent mediators of these systemic sequelae. The aim of our study was to determine the prevalence of H. pylori infection in hypertensive patients and the effects of H. pylori eradication on blood pressure and on digestive symptoms., Materials and Methods: Seventy-two hypertensive patients (34 male and 38 female; mean age 53 +/- 12 years) and 70 normotensive controls (35 male and 35 female; mean age 52 +/- 10 years) were enrolled. All patients were subjected to a first ambulatory blood pressure monitoring (ABPM) at enrollment, a 13C urea breath test and a test for IgG-CagA antibodies, and completed the validated dyspepsia questionnaire. H. pylori-positive patients were treated with triple therapy (amoxicillin, clarithromycin and ranitidine bismute citrate) for 7 days. Control of eradication was assessed by 13C urea breath test, and all patients underwent a second ABPM 6 months after enrollment., Results: H. pylori infection was 55% in hypertensive patients, with 90% CagA positivity, and 50% in controls, with 60% CagA positivity. At the first ABPM, blood pressure values were similar in H. pylori-positive and -negative individuals; positive patients showed a significant increase in pyrosis and epigastric pain compared to negative patients. H. pylori was eradicated in 80% of patients and in 85% of controls. At the second ABPM, we found a statistically significant decrease in 24-hour mean blood pressure values when compared to the first ABPM only in the eradicated hypertensive group., Conclusions: Our study demonstrated a significant decrease in blood pressure values, in particular in diastolic blood pressure values, after H. pylori eradication in hypertensive patients. A high prevalence of CagA positivity was found. The association between cardiovascular disease and H. pylori infection seems pronounced only in CagA-positive patients. The possible links between hypertensive disease and H. pylori infection may involve the activation of the cytokine cascade with the release of vasoactive substances from the primary site of infection, or molecular mimicry between the CagA antigens of H. pylori and some peptides expressed by endothelial cells and smooth muscle cells.

To assess the role of interleukin-6 (IL-6) in migraine, we analyzed the -174 G/C IL-6 gene polymorphism in 268 patients with migraine and 305 controls. No significant difference in the distribution of IL-6 genotypes (chi(2)=0.601, P=0.74) and allelic frequencies (chi(2)=0.024, P=0.876) was found. When patients were subdivided into subgroups (migraine with aura, migraine without aura and mixed headaches), IL-6 alleles were similarly distributed. Comparison of the clinical features of the disease with the -174 G/C IL-6 genotypes showed no significant difference. In conclusion, we found no significant association between the -174 G/C IL-6 polymorphism and the occurrence or the clinical features of migraine.

We compared the clinical, psychological and pharmacological characteristics of patients with familial migraine and patients with sporadic migraine. Five hundred and thirty consecutive new patients attending our Headache Center over a two-year period were involved in the study. The patients were divided into two groups: A. Familial migraine (famM)--at least one first-degree relative affected; B. Sporadic migraine (spoM)--no first-degree relative affected. Four hundred and twenty-four patients (80%) fulfilled the criteria for famM and 106 (20%) for spoM. The patients with famM showed a significantly (p<0.01) earlier age at onset of the disease. No significant difference in all the remaining features examined was found. Our data suggest that famM and spoM represent a single disease entity.

Background: The role of foods as headache precipitants is still matter of debate. Several studies reported that dietary constituents may precipitate migraine attacks. Some authors reported that also tension type headache attacks may be provoked by foods. The purpose of this study was to evaluate the role of foods as headache triggers in both groups of patients., Methods: We compared the role of foods as headache trigger in patients with migraine and tension type headache. Three hundred and nine patients were involved in the study and divided into six groups: 1) migraine without aura, 2) migraine with aura, 3) episodic tension type headache, 4) chronic tension type headache, 5) migraine without aura associated with episodic tension type headache, 6) migraine without aura associated with chronic tension type headache., Results: Approximately one third of the patients reported susceptibility to certain foods. The percentage of food sensitivity was not significantly different between patients with migraine or tension type headache. The foods more commonly reported as headache triggers were alcoholic drinks, chocolate and cheese. No difference in specific food sensitivity between groups was found. The comparison of food-sensitive with food non-sensitive patients showed no significant difference in the clinical features., Conclusions: Our study suggests that foods may trigger not only migraine but also tension type headache attacks.

To investigate the role of apolipoprotein E (APOE) polymorphisms in migraine, we analyzed the APOE genotypes of 241 migraine patients and 587 controls. The results of a Chi-square analysis indicated that APOE alleles were similarly distributed (chi(2)=2.89, P=0.24) between cases and controls. However, we found a significant (P<0.001) increase of the varepsilon2-varepsilon4 genotype in the group of migraine patients. Patients were divided into three subgroups: migraine with aura; migraine without aura; and mixed headaches (migraine associated with tension-type headache). Subgroup analysis showed that the varepsilon2-varepsilon4 genotype was significantly increased only in patients with mixed headaches. The stratification of patients by APOE status did not reveal significant associations with the clinical features of the disease. In conclusion, we observed no significant association between APOE polymorphisms and migraine. The association between the APOE varepsilon2-varepsilon4 genotype and the tension-type headache deserves further evaluation.

Neurological involvement in multiple endocrine neoplasia (MEN) syndrome is uncommon. Notalgia paresthetica (pruritus localized in an area between D2 and D6 dermatomes) is the neurological symptom more frequently described in patients with MEN 2A. The authors report the unusual case of a MEN 2A patient with a brain metastasis from a pheochromocytoma.

Background: Blood pressure is a quantitative multifactorial trait influenced by environmental and genetic determinants. Although several candidate genes have been associated with the development of essential hypertension, the mechanisms of individual susceptibility still remain unclear. Knowledge on the distribution of genetic polymorphisms in different populations is fundamental for the assessment of the predictive value of genetic variation., Methods: We genotyped 300 healthy normotensive subjects from the Italian population for three polymorphisms, at the angiotensinogen (AGT, M and T), angiotensin II type 1 receptor (ATIR, A and C) and angiotensin-converting enzyme (ACE, D and I) genes. Polymorphisms were analyzed by polymerase chain reaction and restriction enzyme digestion. Statistical analysis was performed to verify the agreement with the Hardy-Weinberg equilibrium., Results: The observed allelic distribution was in accordance with estimates reported for Caucasian populations. Variant allelic frequencies were 0.36 for the T and C alleles at the AGT andAT1R locus and 0.47 for the I allele of the ACE gene. AT1R and ACE genotype frequencies were in Hardy-Weinberg equilibrium, while there was a deviation of the AGT genotypes from those predicted by the equation., Conclusions: The studied polymorphisms are largely distributed in the Italian population sample, with a frequency of homozygous subjects for mutant alleles ranging from 9 to 22%. Epidemiology of mutations in the genes involved in blood pressure regulation provides tools to evaluate susceptibility to hypertension.

We evaluated the sensitivity of 5-HT1D receptors in patients with migraine using sumatriptan as a pharmacological probe. The drug inhibits the release of ACTH, cortisol and prolactin and this effect may be used to explore the function of serotoninergic systems in vivo. We administered sumatriptan (6 mg sc) and placebo to 15 migraineurs, during the headache-free period, and to 10 healthy controls. Blood samples were collected -15, 0, 15, 30, 45, 60 and 90 min after injections. Sumatriptan induced a significant (p<0.01) decrease of ACTH, cortisol and prolactin concentrations both in patients with migraine and in controls. The neuroendocrine response was not significantly different in the two groups. Our results suggest that 5-HT1D receptor sensitivity is not altered in migraine.

A subclinical elevation in urinary albumin excretion (UAE) microalbuminuria is frequently seen in essential hypertension. The level of blood pressure appears to be an important factor in the development of microalbuminuria. Moreover there is some evidence to indicate that microalbuminuria may be an early marker of increased cardiovascular risk. Aim of this study was to evaluate the prevalence of UAE in hypertensives with normal left ventricular mass and to study any association with blood pressure level and with possible modification in left ventricular function. A group of 112 subjects diagnosed as having stage 1-2 essential hypertension were included in the study. Patients underwent urinary collection to evaluate UAE and to 24/hours arterial blood pressure monitoring. Moreover a complete echocardiography was performed. According with UAE levels patients were divided into three groups: A: UAE 0-15 mg/24 h, B: UAE 16-29 mg/24 h, C: UAE 30-300 mg/24 h. We found a significant correlation between 24/h SBP, 24/h DBP and UAE. We observed a significant correlation between impaired diastolic function and UAE. UAE is influenced by BP levels with better correlation with 24/h systolic values. UAE is associated with subclinical decrease of left ventricular function and may be an early marker of cardiac involvement.

Objective: To determine whether chronic Helicobacter pylori infection is a risk factor for migraine., Background: Preliminary studies have shown a high prevalence of Helicobacter pylori infection in patients with primary headaches., Methods: One hundred three consecutive patients with migraine were enrolled in the study and compared with a group of 103 matched controls. Helicobacter pylori infection was diagnosed by means of both (13)C-urea breath test and serology., Results: Of patients with migraine, 30.1% were positive for Helicobacter pylori, compared with 31.1% of controls (P = NS). The odds ratio for migraine associated with chronic Helicobacter pylori infection was 0.96 (95% confidence interval, 0.51 to 1.80). Demographic, clinical, and psychological characteristics of Helicobacter pylori-positive migraineurs were compared with those of migrainous patients without infection. Helicobacter pylori-positive patients had a significantly (P<.05) lower incidence of food sensitivity than Helicobacter pylori-negative patients. No significant difference was found in any other feature examined., Conclusions: Our study suggests that chronic Helicobacter pylori infection is not more frequent in patients with migraine than in controls and that infection does not modify clinical features of the disease.

In hypertension both beta-blockers and calcium antagonists are drugs with proved efficacy. Because only half the patients respond to a single drug, even at full dosage, a second hypotensive agent is frequently required to obtain adequate blood pressure control. The combination of a dihydropyridine calcium antagonist and a beta-blocker can be justified by their different mechanisms of action. A randomised double blind parallel group study versus placebo was performed, in order to assess the efficacy of atenolol combined with amlodipine in the treatment of stage I-II essential hypertension not controlled by atenolol alone. Twenty-four-hour arterial blood pressure monitoring showed that amlodipine added to atenolol produced a statistically significant reduction of blood pressure values compared with placebo in patients whose blood pressure was not controlled by atenolol alone. Blood pressure circadian rhythm was unchanged. The reduction of side-effects, obtained by adding a dihydropyridine derivate to a beta-blocker, confirms the effectiveness of this combination.

Background: Troponin I, a specific cardiac muscle protein, has proven to be very helpful in detecting myocardial damage in ischemic heart disease. In order to assess if this laboratory test may also characterize some hypertensive subjects with proven cardiac damage, we compared troponin I serum concentrations of a group of patients affected by systemic hypertension and left ventricular hypertrophy (LVH) with troponin I serum concentrations of hypertensive patients without LVH and with normal controls., Methods: Of 100 hypertensive patients consecutively enrolled in the study, 27 had an increased left ventricular mass by M-mode/two-dimensional echocardiographic examination. Of these, 4 were excluded for significant Holter ST-segment modification. Troponin I was measured in the remaining 23, in 23 age- and sex-matched hypertensive patients with normal left ventricular mass and in 23 normal controls., Results: Troponin I serum concentration was higher than the upper limit of the normal values (0.5 ng/mi) in 12 of the 23 hypertensives with LVH. On the contrary, all hypertensives without LVH and all normal controls had troponin I serum concentration below the upper limit of the normal values. Consequently, the mean troponin I serum value was significantly higher in the group of hypertensive patients with LVH than in the group of patients without LVH (0.88 +/- 0.93 vs 0.27 +/- 0.08 ng/ml, p = 0.002) and in normal controls (0.88 +/- 0.93 vs 0.22 +/- 0.04 ng/ml, p = 0.0001)., Conclusions: Our data indicate that a significant proportion of patients affected by essential hypertension with LVH have slightly elevated troponin I serum concentrations. This test seems to identify two subgroups of hypertensive subjects with LVH, and, considering that troponin I is a marker of myocardial damage, higher serum values probably indicate a more important cardiac involvement in the setting of a hypertensive disease.

Hypertensive urgencies are clinical settings in which a steady therapeutic intervention is needed, but this may be safely stretched over some hours. An appropriate antihypertensive drug to use in an urgency should show a potent but gradual effect: it should reduce BP in a short time and it should be easy to modulate the antihypertensive effect, according to individual needs. Sublingual administration is the easiest way for a therapeutical intervention in an urgency. The use of nicardipine administered sublingually was tested in comparison with nifedipine, during a hypertensive urgency, in 24 hypertensive subjects. The peak effect of nifedipine occurred within 10-20 minutes after the administration, whereas that of nicardipine occurred after 45-50 minutes; nevertheless a significant decrease both in systolic and diastolic blood pressure was already observed 20 min after nicardipine administration. The hypotensive effect of nicardipine was longer lasting than that of nifedipine. Some adverse effects were observed in the group receiving nifedipine, whereas no side effects were described by patients receiving nicardipine.

Aim of the study was to assess the effectiveness and tolerability of sublingual captopril (SLC) versus sublingual nifedipine (SLN) in treating hypertensive emergencies. During hypertensive crises (systolic blood pressure exceeding 200 mmHg and diastolic blood pressure exceeding 115 mmHg) forty hypertensive patients received either 25 mg of SLC or 10 mg of SLN in a randomized single blind fashion. Blood pressure and heart rate were then controlled after 5, 10, 15, 20, 30, 45, 60, 120 min. and, in 18 cases, up to the 8th hour from the administration. Our results showed: 1) a satisfactory control of the hypertensive crises in 80% of patients treated with SLC with a significant blood pressure reduction after 10 min. (13/8 mmHg, p less than 0.02), while the maximum hypotensive effect was achieved after 30 min. (52/36 mmHg, p less than 0.001); SLN was able to reduce blood pressure in 90% of all the cases, with a significant reduction after 5 min. (15/11 mmHg, p less than 0.02) and hypotensive peak after 20 min (57/38 mmHg, p greater than 0.001); 2) no significant differences for hypotensive effectiveness between the two groups, but with SLC having a mildly delayed onset of action when compared to SLN; 3) antihypertensive effect lasting for about 6 hours in patients treated with SLC and blood pressure progressively raising after 4 hours in patients who received SLN; 4) a significant correlation between blood pressure reduction and blood pressure before drug administration in both groups; a significant correlation between pretreatment PRA and antihypertensive effect in the SLC group. We conclude that both drugs are effective and useful in treating hypertensive emergencies. Anyway we think that in severe forms SLN should be preferred for the shorter time preceding onset of action.

The concentration of plasma fibrinogen increases with age and is particularly elevated in subjects with vascular changes due to atherosclerosis. Fibrinogen, which is the meeting point of the "cascade" of the coagulation factors and an important regulating factor of plasma viscosity, occupies a key position in atherosclerotic vascular pathology. This indicates the necessity to keep its value within normal limits, to avoid the clinical development of the disease or improve its evolution. Thus, frequent checks of the fibrinogenemia are necessary at various ages even if this means a big organizational burden. However, this checking can be facilitated by using automatic techniques, such as the immunonephelometric method, with which it is possible to carry out a large number of determinations in a short time.

Although ambulatory blood pressure monitoring has been used widely for the evaluation of antihypertensive treatment, little information is available regarding the comparison between this method and casual BP measurement during drug trials. In our study, we tested the efficacy of a new formulation of verapamil, 240 mg sustained-release tablets, and compared the degree of BP reduction as detected by casual (standard mercury manometer) and by 24-hour ambulatory recording (Spacelab ICR 5300). A statistically significant fall in casual BP was observed after verapamil with respect to placebo. Moreover, 24-hour, waking and sleeping ambulatory BPs were significantly reduced by verapamil. The mean BP reduction was similar for office (20.1/16.1 +/- 4.3/3.1 mmHg) and for day-time ambulatory monitoring (13.4/10.7 +/- 4.2/1.9 1.9 mmHg), but no correlation was found between BP fall recorded by the two techniques for individual subjects. This study suggests that sustained-release verapamil is an effective antihypertensive drug. Individual mean BP reduction outside the clinic may not be predicted from office readings and therefore ambulatory BP recording seems to provide a better basis for testing the efficacy of drugs.

Somatostatin is a cyclic tetradecapeptide widely distributed in the human cells; it has many physiological effects. Synthetic somatostatin, actually employed in some clinical conditions, was administered intravenously to normal and arteriopathic subjects. Rheography and plethysmography of lower limbs were performed before, during and after administration. A marked improvement of blood flow and a reduction of heart rate was observed after somatostatin infusion. Some hypotheses about the mechanism of action of somatostatin are discussed, especially the action on the sympathetic nervous system or the calcium-antagonist effect on the blood vessels.