A phase 2a randomized controlled study to evaluate the pharmacokinetic, safety, tolerability and clinical effect of topically applied Umeclidinium in subjects with primary axillary hyperhidrosis.

BACKGROUND: Hyperhidrosis is a common medical condition which can have a significant impact on quality of life. Umeclidinium (UMEC) is a long-acting muscarinic antagonist (LAMA) developed as a dermal formulation. OBJECTIVES: This 2-week, double-blind, randomized, vehicle-controlled study evaluated systemic exposure, safety and tolerability of topically administered UMEC in subjects with primary axillary hyperhidrosis. Clinical effect was a secondary objective, measured by gravimetry and the hyperhidrosis disease severity scale (HDSS). Vehicle was included to evaluate safety. METHODS: Twenty-three subjects were randomized to either 1.85% UMEC (N = 18) or vehicle (N = 5) once daily. RESULTS: Measurable plasma concentrations were observed in 78% of subjects after the treatment. Nine subjects (50%) on UMEC and two subjects (40%) on vehicle reported AEs, most commonly application site reactions. At Day 15, seven subjects (41%) in UMEC and two subjects (40%) in vehicle had at least a 50% reduction in sweat production. Eight subjects (47%) in UMEC and one subject (20%) in vehicle had at least a two-point reduction in HDSS. No comparisons of treatment arms were planned prospectively. CONCLUSIONS: The measurable exposure, acceptable safety and preliminary clinical activity observed in this proof-of-concept study suggest the potential clinical utility of topical UMEC in subjects with axillary hyperhidrosis.

A recent epidemiological cluster of acute hepatitis B genotype F1b infection in a restricted geographical area of Italy.

In this study, by phylogenetic analysis, we identified an epidemiological cluster involving eight individuals diagnosed with acute hepatitis B virus (HBV) infection related to unprotected sexual intercourse in a restricted area of central Italy (time period: 2011-2014). Notably, these patients (six of eight Italians) were infected by subgenotype F1b, which is not commonly found in western countries. Ultra-deep pyrosequencing confirmed a superimposable composition of HBV quasi-species in these patients. Despite the availability of effective vaccination, this study highlights the importance of not underestimating the risk of HBV infection, of continuing to set up surveillance programmes for HBV infection, and of investigating the pathogenetic potential of these atypical genotypes.

Acute urinary retention due to HSV-1: a case report.

Complications in urinary tract nervous routes due to herpes viruses as VZV and HSV-2 are well known. Acute urinary retention and chronic neuropathic pain are not rare when sacral dermatomes are involved by these viruses. However, an analogous condition has not yet been clearly ascribed to HSV-1 infection. We present a 32-year-old immunocompetent patient with fever, lumbar pain and acute urinary retention who had never had herpetic clinical manifestations. Urodynamic studies diagnosed a neurologic bladder with an absent filling sensation. Cystoscopic assessment revealed the presence of reddened and isolated small mucosal areas in the bladder walls. The search for herpes viruses in plasma and CSF by PCR assay were positive for HSV-1. After treatment with antiviral therapy the disease resolved. Intermittent catheterization was necessary and voiding dysfunction resolved after three weeks by its appearance. Neurological damage to the central nervous system (CNS) and/or PNS due to HSV-1 seems to be the most likely reason. The course of disease was benign and self-remitting.

Study of immune alterations in patients with chronic fatigue syndrome with different etiologies.

The Chronic Fatigue Syndrome (CFS) is characterized by symptoms lasting for at least six months and accompanied by disabling fatigue. The etiology of CFS is still unclear. At the National Center for Study of the Infectious Diseases Department of the Chieti University some immune investigations were performed with the purpose of detecting markers of the disease. CD4+, CD8+, NK CD56+ and B CD19+ lymphocytes were studied in 92 male and 47 female patients and in 36 control subjects. CFS patients were divided in three groups with a post-infectious onset (PI-CFS), an non post-infectious onset (NPI-CFS) and a non post-infectious onset with associated infections (NPI-CFS + AI). Both CD4+ and CD8+ lymphocytes were reduced in the CFS patients. However, the CD4+/CD8+ ratio was increased in the CFS patients without difference between males and females. CD56+ cells of CFS patients were also reduced. In particular, blood CD56+ cells counts were significantly higher in PI-CFS patients than in the NPI-CFS subjects. These data confirm our preliminary results suggesting a key-role of a dysfunction of the immune system as a precipitating and-or perpetuating factor of the syndrome.

Interleukin-4 and interferon-gamma production during HIV-1 infection and changes induced by antiretroviral therapy.

Several lines of evidence indicate that a switch of the cytokine pattern from a predominant type 1 (antiviral and cell mediated response) to type 2 (polyclonal humoral immune response) occurs during the course of Human Immunodeficiency Virus-1 (HIV-1) infection, and represents a key event in the progression of immunodeficiency and dysregulated immune activation. We proposed to further investigate this immunological aspect of HIV-1 disease, in naive and in patients treated with Highly Active Antiretroviral Therapy (HAART). The prototypic cytokines chosen were Interleukin (IL)-4 and Interferon-gamma (IFN-gamma), whose in vitro production was determined in mononuclear cell cultures stimulated with different T lymphocyte mitogenic agents (anti-CD3, Phytohaemoagglutin-P -PHA-, E. coli B04/035 Lipopolysaccharide -LPS-). We classified all the patients on the basis of the number of CD4+ lymphocytes and we found a progressive, even if not significant decrease in the baseline production of IFN-gamma with the progression of the immunodeficiency. The mean value of baseline IFN-gamma in the group of patients with CD4+>500 cells/microL was 7.79 +/- 3.1 pg/mL while in the group with CD4+<200 cells/microL it was 4.66 +/- 2.22. We didn't find significant differences in the baseline production of IL-4 in these groups and in IFN-gamma and IL-4 production in LPS-stimulated cultures. We also re-assessed 12 patients after one year's follow-up. They presented a significant increase in IFN-gamma production compared to the first assessment in the LPS-stimulated cultures (baseline IFN-gamma 2.87 +/- 1.17 pg/mL, after 12 months 19.15 +/- 5.19 pg/mL; p= 0.03). In the 12 patients in follow-up IL-4 production showed a decreased in PHA-stimulated cultures with mean values of 16.65 +/- 14.32 pg/mL at baseline and 6.54 +/- 6.54 pg/mL after follow-up. These results highlight the immunorestoring effects of HAART. IL-4 production was lower in the treated subjects compared to the naive ones in PHA-stimulated cultures (mean values: IL-4=13.42 +/- 11.08 pg/mL in the naive patients and 9.75 +/- 65 pg/mL in the treated patients). The IFN-gamma values in anti-CD3 stimulated cultures were also higher in the treated patients, but this increase was not significant.

-Dual nucleoside therapy for HIV infection: analysis of results and factors influencing viral response and long term efficacy.

We performed a retrospective analysis of our experience with dual nucleoside regimens to look for predictors of long term benefit. The study evaluated a cohort of 68 HIV-infected patients treated at 3 Italian hospital-based facilities. The results were evaluated using univariate and multivariate statistical analysis. Fourty-three males and 25 females were treated for 22 +/- 14 months. Sixty three patients (92.6%) suffered no or low-grade side-effects. Thirty-four patients (50%) reached a viral load <400 copies/ml (undetectable). Viremia remained persistently undetectable in 9 cases (13.2%). Variable relapses of viremia were seen in 13 patients (19.1%) even though their therapys were not modified. Eight patients (11.8%) showed relapsing viremias persistently around or below 10,000 copies/ml. All patients reaching undetectable viremia but one showed increasing or stable CD4+ cell counts. Factors predicting favourable response were: pre-treatment CD4+ T-cells >150/microl, pre-treatment viremia <50,000 copies/ml, pre-treatment lymphocytes >1,500/microl, and no previous exposure to NRTI. Total lymphocyte counts and CD4+ T-cells showed a significant correlation. Dual NRTI regimens may be still considered for patients unable to tolerate HAART regimens and presenting with favourable predictors of response.

Detection of rifampin resistance by single-strand conformation polymorphism analysis of cerebrospinal fluid of patients with tuberculosis of the central nervous system.

Mutations in a 69-bp region of the rpoB gene of Mycobacterium tuberculosis are associated with rifampin resistance (Rif[r]). These have been detected with mycobacterial DNA extracted from bacterial suspensions or respiratory specimens that were acid-fast smear positive. We experimented with a strategy for the rapid detection of Rif(r) in cerebrospinal fluid (CSF) samples. The strategy involves the amplification of the 69-bp region of rpoB by means of PCR and the identification of nucleotide mutations by single-strand conformation polymorphism (SSCP) analysis of the amplification products. Sixty-five CSF specimens collected from 29 patients (19 patients were coinfected with human immunodeficiency virus) with culture or autopsy-confirmed (22 patients) or highly probable (7 patients) tuberculosis of the central nervous system (CNS-TB) were processed. Amplified products suitable for evaluation by SSCP analysis were obtained from 37 CSF specimens from 25 subjects (86.2%). PCR-SSCP of CSF correctly identified the rifampin susceptibility phenotype of isolates from all 17 patients for whom the results of susceptibility tests carried out with strains cultured from CSF or respiratory samples were available. Moreover, this assay revealed the rifampin susceptibility genotype of isolates from the eight patients (three patients with culture-confirmed CNS-TB and five patients in whom CNS-TB was highly probable) for whom no susceptibility test results were available; the PCR-SSCP data obtained for these patients were concordant with the outcome after a standard antituberculosis treatment. The evolution of a mutation in the rpoB gene was documented in a patient during the course of treatment. PCR-SSCP analysis of CSF seems to be an efficacious method of predicting Rif(r) and would reduce the time required for susceptibility testing from approximately 4 to 8 weeks to a few days.

Time-courses of p-CPA-induced depletion of brain serotonin and muricidal aggression in the rat.

p-Chlorophenylalanine is known to selectively decrease brain serotonin and to induce muricidal aggression in previously docile rats. With regard to the substance's relatively time-limited effect on brain serotonergic system, the neurochemical activity of p-CPA on tryptophan, serotonin and 5-hydroxyindoleacetic acid on seven discrete areas of the rat brain is studied in parallel to the time-course of muricidal aggression induced by the drug. Evidence indicates that, following the disruption of brain serotonergic inhibitory control, muricidal aggression becomes a stable behavior, probably on account of its self-reinforcing property.