Phase I Study in Healthy Women of a Novel Antimycotic Vaginal Ovule Combining Econazole and Benzydamine.

Purpose: A novel fixed-dose combination of 150 mg of econazole with 6 mg of benzydamine formulated in vaginal ovules was investigated in a randomised, double-blind, four-parallel group, tolerability, and pharmacokinetic Phase I study in healthy women. Methods: The fixed-dose combination was compared to econazole and benzydamine single-drug formulations and with placebo after daily applications for 3 consecutive days. Safety and tolerability were evaluated recording the adverse drug reactions, local and general tolerability scores, clinical laboratory assays, and vital signs. Econazole, benzydamine, and its metabolite benzydamine N-oxide pharmacokinetics were investigated after single and multiple applications. Results: Local reactions were generally absent. Pruritus and pain at the application site were infrequently reported. According to the subjects' evaluations, the overall tolerability of the ovules was rated as excellent or good. No significant effect of any treatment on laboratory parameters, vital signs, body weight, vaginal pH, or ECG was observed. Very low econazole, benzydamine, and benzydamine-N-oxide concentrations were measured in plasma, though quantifiable in almost all samples. Conclusion: The tested fixed-dose combination showed a good safety profile consistently with the known tolerability of both active substances. In addition, the confirmed low bioavailability of the drugs excludes the possibility of any accumulation effects and limits the risk of undesired systemic effects. This trial is registered at ClinicalTrials.gov with the identifier NCT02720783 last updated on 07 February 2017.

Gait pattern classification in children with Charcot-Marie-Tooth disease type 1A.

Gait pattern classification may assist in clinical decision making and cluster analysis (CA) has been often adopted to this aim. The goal of this study was to identify, through CA, typical walking patterns in a group of 21 young subjects with CMT1A, a hereditary progressive neuropathy, and to study possible correlation with the disease's clinical status. The protocol included kinematic/kinetic analysis of natural walking and more demanding locomotor tasks, i.e. toe- and heel-walking. Hierarchical cluster analysis was carried out on parameters related to primary signs (foot-drop and push-off deficit) and, separately, to compensatory mechanisms at proximal (pelvis, hip and knee) or distal (ankle) level. CA on primary signs during natural walking identified three clusters: (1) pseudo-normal patients (PN), not significantly different from controls; (2) patients showing only foot-drop (FD); (3) patients with foot-drop and push-off deficit (FD&POD). Patients belonging to the PN subgroup showed distal abnormalities during heel-walking. The FD&POD subgroup was associated to a significantly worse clinical score (CMTES, p<0.05). The main compensatory strategies, which occurred independently from primary clusterization, included augmented hip/knee flexion in swing (steppage) and early ankle plantarflexion at mid stance (vaulting). We concluded that, although a number of young CMT1A patients do not show typical primary deviations during natural walking, they do show significant abnormalities in more demanding locomotor tasks that should be therefore considered. It is also hypothesized that progression of this degenerative condition may be associated to the migration of patients to more severe clusters, with possible appearance of compensatory strategies.

Reliability of instrumented movement analysis as outcome measure in Charcot-Marie-Tooth disease: results from a multitask locomotor protocol.

Some neurodegenerative diseases at early stage may not drastically affect basic gait ability, whereas more demanding locomotor tasks are more prone to disease-induced abnormalities. In this study, we evaluated the interday test-retest reliability, 4-6 weeks apart, of instrumented movement analysis on a group of 20 subjects with Charcot-Marie-Tooth (CMT) disease considering a set of kinematic and kinetic curves and related parameters obtained during natural walking (NW) and faster walking, heel and toe-walking, step ascending and descending. Results showed that the reliability was good for NW, with the exception of trunk curves, pelvic tilt and EMG profiles (moderate reliability), and trunk ROM in sagittal/transverse plane (poor reliability). Comparing our results with literature, CMT patients did not present a greater variability during NW than healthy subjects or patients with diseases of CNS. Additional locomotor tasks showed a slight reduction of reliability, although the moderate-to-good level shown in NW was almost never reduced to poor. Most of SEM values (absolute measurement errors) were smaller than 5°, a clinically acceptable threshold. In particular THS, an ankle joint related parameter computed across heel and toe-walking tasks, showed an optimal reliability (ICC=0.95, SEM=2.7°) and correlation with CMT clinical scores. Toe and heel-walking and step ascending tasks maximised the number of parameters with a moderate-to-good correlation with patients' clinical status. We concluded that, in addition to natural walking, more challenging locomotor tasks are good candidates to provide reliable and sensitive outcome measures for CMT patients.

Treatment with bindarit, an inhibitor of MCP-1 synthesis, protects mice against trinitrobenzene sulfonic acid-induced colitis.

OBJECTIVE: Chemokines play a fundamental role in trafficking and activation of leukocytes in colonic inflammation. We investigated the ability of bindarit, an inhibitor of monocyte chemoattractant protein-1 (MCP-1/CCL2) synthesis, to inhibit chemokine production by human intestinal epithelial cells (HT-29) and its effect in trinitro-benzene sulfonic acid (TNBS)-induced colitis in mice. MATERIALS AND METHODS: HT-29 cells were incubated with bindarit in the presence of TNF-alpha/IFN-gamma and 24 h later supernatants were collected for MCP-1, IL-8 and RANTES measurement. A 1 mg enema of TNBS was given to BALB/c mice, and bindarit (100 mg/kg) was orally administered twice daily starting from two days before colitis induction. Weight loss, histology, and MCP-1 level and myeloperoxidase (MPO) activity in colon extracts were assessed. RESULTS: In HT-29 cells, bindarit concentration-dependently and selectively inhibited MCP-1 secretion (as well as mRNA expression) primed by TNF-alpha/IFN-gamma. Moreover treatment with bindarit reduced clinical and histopathological severity of TNBS-induced colitis. These effects were associated with significant inhibition of MCP-1 and MPO in colon extracts. CONCLUSIONS: Bindarit exhibits a potent bioactivity in reducing leukocyte infiltration, down-regulating MCP-1 synthesis, and preventing the development of severe colitis in a mice model of TNBS-induced colitis. These observations suggest a potential use of MCP-1 synthesis blockers in intestinal inflammation in humans.

[Usefulness of directional power Doppler sonography in the ultrasound-guided percutaneous native kidney biopsy]. / Utilita' dell'Eco Power Doppler direzionale nella biopsia transcutanea su rene nativo.

BACKGROUND: The study was aimed to analyze the pattern of bleeding throughout the kidney tissue after renal biopsy and evaluate its relationship with the onset of renal biopsy side effects by using directional power-Doppler sonography. PATIENTS: Eighty-five consecutive subjects with clinical evidence of renal disease underwent to percutaneous renal biopsy using directional power Doppler sonography. In each patient, the pattern of kidney hemorrhage immediately after the renal biopsy was evaluated. RESULTS: Fifty-seven patients, representing 67% of all biopsies performed, evidenced renal bleeding lasting 5.3+/-5.7 min; fifty-five patients, representing 65% of all biopsies, developed a post biopsy hematoma (x = 2.9+/-2.0 cm); 36% of patients developed a perirenal hematoma (x = 1.8+/-2.1 cm). A subcapsular hematoma was experienced by 45% of patients (x = 2.7+/-1.1 cm); 16% of these patients had a combined perirenal-subcapsular hematoma; 5% of hematomas were larger than 5 cm. Hematoma dimensions were related to the length of bleeding (r = 0.6331; p < 0.0001). Hemoglobin and hematocrit levels significantly reduced from 12.7+/-2.3 g/dL to 11.7+/-2.3 g/dL (-7%, p < 0.0001) and 37.6+/-6.5% to 35.4+/-6.5% (-6%, p < 0.0001) respectively, and such variations were related to the hematoma size (Delta Hb: r = -0.5171; p < 0.0001; Delta Htc: r = -0.3465; p < 0.0001). CONCLUSIONS: This study demonstrates that directional power Doppler sonography allows medical personnel to clearly evidence all renal biopsy-related side effects and identify, through the evaluation of renal bleeding immediately after the kidney biopsy, those patients who will develop renal hematomas.

[Traditional ultrasonography, directional Doppler power, and levovist in the morphological and functional evaluation of single kidney]. / Ecografia tradizionale, power Doppler direzionale e Levovist nello screening morfofunzionale del monorene.

Either the color and the power Doppler have given important information on renal haemodynamics, but these methods are limited. The power directional Doppler (pdD) surpasses such limits; again, administration of Levovist increases the intensity of vascular signal. The aim of this study is the evaluation, in subjects with a solitary kidney, but without evident nephropathies, the morphology, the cortical vascularization and the functional status of the kidney. We studied 21 patients divided into three groups. Group A: subjects with normal renal function; group B: patients with caliceal and pielic dilation; group C: patient with chronic renal failure (CRF). In all subjects, a pdD was effected. Only in three patients it was necessary to administer Levovist, in order to emphasize the parenchymal vascularization. The A group subjects, on echographic B-mode examination, presented a normal morphology and volume of the kidney; on pdD exam, a regular intense and homogeneous parenchymal vascularization, with resistance index (RI) = 0.53 divided by 0.66. In B group, pdD showed an irregular vascularization, with RI > 0.7; also the glomerular filtration rate (GFR) was reduced (70 ml/min). In C group, at the pdD it was relevant a reduced and irregular vascularization in whole renal tissue. If possible, the echographic B-mode examination must be completed with the pdD, with or without Levovist, in order to identify unknown renal pathologies, moreover in subjects with a single kidney.

Short-term effects of low protein-normal sodium diet on renal function in chronic renal failure.

To investigate the short-term renal effects of protein restriction and unchanged salt intake in chronic renal failure (CRF), patients with moderate CRF (creatinine clearance 41 +/- 5 ml/min) and healthy controls (CON) ate a normal protein diet (NPD) for four weeks, and thereafter a low protein diet (LPD, 0.4 g/kg body wt/day) for three weeks. The two diets were isocaloric and with a salt intake of 10 to 13 g/day. No differences in body weight, serum proteins and plasma sodium were recorded throughout the study. During LPD, inulin and PAH clearances in CON demonstrated a progressive 25% decline of basal GFR and RPF; on the contrary, in CRF, basal renal function did not change in presence of a significant reduction of proteinuria. In CON patients after protein restriction, fractional free-water generation (CH2O/CIn) and fractional urinary excretion of sodium (FENa) measured under maximal water diuresis increased progressively, both being doubled at the end of LPD, while in CRF, CH2O/CIn did not change and FENa values remained unmodified and much higher (above 4%) than in CON after both diets. The renal response to an acute oral protein load (OPL) and i.v. low-doses of dopamine (D) was measured at the end of each period; in the two groups, GFR and RPF significantly increased following OPL + D after both diets. In CRF, however, the vasodilatory response was blunted overall being reduced after both LPD and NPD, and, unlike CON, it did not increase after LPD.(ABSTRACT TRUNCATED AT 250 WORDS)