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Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder associated with an increased risk of developing a variety of benign and malignant tumors. Fifteen to 20% of children with NF1 are diagnosed with an optic pathway glioma (NF1-OPG) before 7 years of age, and more than half of them experience visual decline. At present, no effective therapy is available for prevention, restoration, or even stabilization of vision loss in subjects affected by NF1-OPG. This paper aims to review the main emerging pharmacological approaches that have been recently assessed in preclinical and clinical settings. We performed a search of the literature using Embase, PubMed, and Scopus databases to identify articles regarding NF1-OPGs and their treatment up to July 1st, 2022. The reference lists of the analyzed articles were also considered a source of literature information. To search and analyze all relevant English articles, the following keywords were used in various combinations: neurofibromatosis type 1, optic pathway glioma, chemotherapy, precision medicine, MEK inhibitors, VEGF, nerve growth factor. Over the past decade, basic research and the development of genetically engineered mice models of NF1-associated OPG have shed light on the cellular and molecular mechanisms underlying the disease and inspired animal and human testing of several compounds. A promising line of research is focusing on the inhibition of mTOR, a protein kinase controlling proliferation, protein synthesis rate and cell motility that is highly expressed in neoplastic cells. Several mTOR blockers have been tested in clinical trials, the most recent of which employed oral everolimus with encouraging results. A different strategy aims at restoring cAMP levels in neoplastic astrocytes and non-neoplastic neurons, since reduced intracellular cAMP levels contribute to OPG growth and, more importantly, are the major determinant of NF1-OPG-associated visual decline. So far, however, this approach has only been attempted in preclinical studies. Stroma-directed molecular therapies – seeking to target Nf1 heterozygous brain microglia and retinal ganglion cells (RGCs) – are another fascinating field. Microglia-inhibiting strategies have not yet reached clinical trials, but preclinical studies conducted over the last 15 years have provided convincing clues of their potential. The importance of NF1-mutant RGCs in the formation and progression of OPGs also holds promise for clinical translation. The evidence of Vascular Endothelial Growth Factor (VEGF)- Vascular Endothelial Growth Factor (VEGFR) signaling hyperactivity in pediatric low-grade gliomas prompted the use of bevacizumab, an anti-VEGF monoclonal antibody, which was tested in children with low-grade gliomas or OPGs with good clinical results. Neuroprotective agents have also been proposed to preserve and restore RGCs and topical eye administration of nerve growth factor (NGF) has demonstrated encouraging electrophysiological and clinical results in a double-blind, placebo-controlled study. Traditional chemotherapy in patients with NF1-OPGs does not significantly ameliorate visual function, and its effectiveness in halting tumor growth cannot be considered a satisfactory result. Newer lines of research should be pursued with the goal of stabilizing or improving the vision, rather than reducing tumor volume. The growing understanding of the unique cellular and molecular characteristics of NF1-OPG, coupled with the recent publication of promising clinical studies, raise hope for a shift towards precision medicine and targeted therapies as a first-line treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose: We evaluated the effects of 1-(3',4'-dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a new gamma-secretase modulator, on brain beta-amyloid pathology and spatial memory in transgenic mice expressing the Swedish and London mutations of human amyloid precursor protein (hAPP).Experimental Approach: Sixty 6-month-old hAPP mice were treated for 6 months with CHF5074 or ibuprofen (375 ppm in the diet) or standard diet. Twenty-one wild-type mice received standard diet.Key Results: Compared with transgenic controls, CHF5074 treatment significantly reduced the area occupied by plaques in cortex (P = 0.003) and hippocampus (P = 0.004). The number of plaques were also reduced by CHF5074 in both cortex (P = 0.022) and hippocampus (P = 0.005). Plaque-associated microglia in CHF5074-treated animals was lower than in transgenic controls in cortex (P = 0.008) and hippocampus (P = 0.002). Ibuprofen treatment significantly reduced microglia area in cortex and hippocampus but not beta-amyloid burden. On the last day of the Morris water maze, transgenic controls performed significantly worse than the non-transgenic animals and the CHF5074-treated transgenic mice, on the swimming path to reach the hidden platform. Ibuprofen-treated animals did not perform significantly better than transgenic controls.Conclusions and Implications: Chronic CHF5074 treatment reduced brain beta-amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel gamma-secretase modulator is a promising therapeutic agent for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the efficacy of cimetropium bromide, a new antimuscarinic compound, in relieving symptoms of patients with irritable bowel syndrome over a three month period. Seventy consecutive outpatients were given cimetropium (50 mg tid) or placebo according to a double blind, randomised, parallel groups design. Symptoms were evaluated initially and at monthly intervals up to the end of the study period. One patient receiving placebo withdrew because of treatment failure. Pain score decreased by 40, 66, 85% in the cimetropium group, at the end of the first, second and third months respectively, compared with 26, 32 and 52% reductions among controls (p = 0.0005). At the end of treatment there was a 86% reduction in the number of abdominal pain episodes per day in the cimetropium group compared with 50% in the placebo group (p = 0.001). Constipation and diarrhoea scores decreased by 59 and 49% in the cimetropium treated patients, compared with 37 and 39% in controls, the differences between being not significant. At the end of the study 89% of the patients treated with cimetropium considered themselves as globally improved as opposed to 69% in the placebo group (p = 0.039). The corresponding 95% confidence intervals for the differences between the proportion of improved patients in the two groups were from 11% to 29%. Six patients taking cimetropium complained of slight dry mouth. The results of this study showed that cimetropium bromide is effective in relieving pain in patients with irritable bowel syndrome. [ABSTRACT FROM PUBLISHER]

As relatively little is known of human colonic motor activity either in health, or in pathological conditions, we investigated mass movements in 14 chronically constipated patients and 18 healthy volunteers. Mass movements were recorded from proximal and distal colon during 24 h (12 noon-12 noon) by a colonoscopically positioned multilumen manometric probe and low compliance infusion system. Patients and controls differed significantly in the number (mean 2.6 (0.7) v 6.1 (0.9) (SE), p = 0.02) and duration (mean 8.2 (1.6) v 14.1 (0.8) s, p = 0.04) of mass movements. The data suggest that one pathophysiological mechanism of constipation may be decreased propulsive activity. A circadian pattern, with a significant difference between day and night distribution, was documented in both groups. The patients reported decreased defecatory stimulus concomitant with the mass movements. [ABSTRACT FROM PUBLISHER]

The concentrations of rufloxacin in the bronchial mucosal, pulmonary epithelial lining fluid and alveolar macrophages were determined in specimens obtained at fibreoptic bronchoscopy. A single oral dose of rufloxacin 400 mg was administered and the samples obtained in the following 72 h. The mean peak serum concentration was 3.56 mg/L, yet the agent was concentrated 1.8-fold in bronchial mucosa, 21.6-fold in alveolar macrophages and 7.7-fold in epithelial lining fluid (as measured by AUC ratios). [ABSTRACT FROM AUTHOR]

The pharmacokinetics of rufloxacin after a single 400 mg oral dose were studied in eight volunteers, measuring plasma, inflammatory fluid and urine concentrations. Mean peak plasma concentrations of 4.4 mg/L were achieved at a mean time of 1.9 h after administration. The mean plasma elimination half-life was 28.2 h. Mean peak levels in inflammatory fluid reached 3.2 mg/L after 3.5 h, and 30.7% of the dose was eliminated in urine by 96 h. The apparent mean volume of distribution of rufloxacin, at steady state, was 109.5 L. The mean percentage penetration of rufloxacin into the inflammatory exudate, as measured by ratios of AUC0-50 h was 90%. [ABSTRACT FROM AUTHOR]

Cimetropium bromide is an antimuscarinic compound with antispasmodic properties. Its effect on meal-stimulated sigmoid motor activity in 30 patients with the irritable bowel syndrome, mainly with pain and constipation, has been evaluated. The mechanical activity of the sigmoid colon was recorded with a probe with three open-tipped tubes ending 45, 30, and 15 cm from the anal margin. After a recording period of 60 min, 5 mg cimetropium bromide or saline was given i.v., according to a randomized, double-blind design 5 min before a 1000 calorie meal, and motility was then recorded for 2 h. The meal caused a significant increase in motor activity for 90 min in the saline-treated group. Cimetropium bromide abolished the peak of motor activity 10-20 min after the meal and significantly inhibited postprandial colonic motility for at least 2 h ( p<0.01). This effect provides a rationale for the use of cimetropium bromide in treatment of the irritable bowel syndrome. [ABSTRACT FROM AUTHOR]