Lymphotonic activity of Ruscus extract, hesperidin methyl chalcone and vitamin C in human lymphatic smooth muscle cells.

OBJECTIVE: Besides actions including their venotonic, anti-inflammatory, and anti-oxidant effects, venoactive drugs are expected to act on edema via their action on lymphatics. The objective of this study was to evaluate the effect of the combination of Ruscus, hesperidin methyl chalcone and Vitamin C (Ruscus/HMC/Vit C) on intracellular calcium mobilization and contraction of human lymphatic smooth muscle cells (LSMCs) to better characterize the mechanism of its lymphotonic activity. METHODS: Calcium mobilization was evidenced by videomicroscopy analysis of the fluorescence emitted by a specific Ca2+ sensitive dye and measured after injection of Ruscus/HMC/Vit C at 0.1, 0.3, 1.0, and 3.0 mg/mL into LSMCs. RESULTS: Ruscus/HMC/Vit C induced a strong and reproducible concentration-dependent calcium mobilization in LSMCs. On the contrary, another venoactive drug used as comparator, micronized purified flavonoid fraction (MPFF), did not induce calcium mobilization whatever the tested concentration. CONCLUSION: Although alternative mechanisms of action may result in potential lymphotonic effects, the efficacy of lymphotonic products is nonetheless related to their stimulating effect on the contractile activity of the smooth muscle cells surrounding lymphatic vessels. In the light of the results obtained in this study, the direct effect of Ruscus/HMC/Vit C on LSMC contraction may partially explain its clinical efficacy on lymphotonic activity, as has been observed in terms of objective signs of edema as reported in the recent guidelines on chronic venous disease.

Bladder telemetry: A new approach to evaluate micturition behavior under physiological and inflammatory conditions.

AIMS: To establish a new approach to cystometry using telemetry in conscious rats and to use this technique to determine the role of conscious decision making processes with respect to the initiation of voiding in physiological, inflammatory, and painful conditions. METHODS: The pressure transducer of a telemetric transmitter was implanted in the dome of the urinary bladder. After a recovery period of at least 1 month, several investigations of urodynamic parameters were performed after diuresis activation by a pulse of furosemide. The model was characterized by tolterodine and mirabegron under physiological conditions and same animals were reused to evaluate the modification of the voiding pattern under bladder inflammation induced by cyclophosphamide. RESULTS: The quality of traces and measurement of parameters recorded telemetrically were comparable to those with conventional cystometry. Furosemide induced a reproducible transient increase of urine production and a series of voids that persisted for 60 min. Tolterodine reduced the amplitude of micturition contractions although mirabegron was devoid of any effect. Seven hours after injection of CYP, voiding frequency increased significantly and the micturition amplitude contraction was not altered. However, the mean volume voided during individual micturitions and the total voided volume decreased. During a second exposure to furosemide 24H after CYP injection, the micturition pattern returned to control, however, the micturition volume was still lower than in control. CONCLUSION: This telemetric model appears to be as accurate as previously described in conscious conventional cystometry, and allows the repeated evaluation of compounds which may modulate the voiding patterns. Neurourol. Urodynam. 36:308-315, 2017. © 2016 The Authors. Neurourology and Urodynamics published by Wiley Periodicals, Inc.

V0162 a new long-acting bronchodilator for treatment of chronic obstructive lung diseases: preclinical and clinical results.

BACKGROUND: Long acting bronchodilators are the standard of care in the management of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the efficacy and safety of V0162, a novel anticholinergic agent with bronchodilator properties, in preclinical models and in patients with COPD. METHODS: Guinea pigs were used to evaluate the impact of V0162 on the acetylcholine or histamine-induced bronchoconstriction. V0162 was also investigated in an allergic asthma model on ovalbumin-sensitized guinea pig. For clinical investigations, healthy volunteers were included in a dose-escalation, randomized, placebo-controlled phase I study to determine the maximal tolerated dose, followed by a randomized, placebo-controlled, cross-over phase II study in patients with COPD. V0162 was given via inhalation route. The objectives of the phase I/II study were to assess the safety and efficacy of V0162, in terms of bronchodilation and reduction in hyperinflation. RESULTS: Preclinical results showed that V0162 was able to prevent bronchoconstriction induced either by acetylcholine or histamine. V0162 reversed the bronchoconstriction and airway inflammation caused by ovalbumin challenge in sensitized guinea pigs. In the healthy volunteers study, 88 subjects were enrolled: 66 received V0162 and 22 received placebo. No particular safety concerns were raised. The maximal tolerated dose was not reached and the dose escalation was stopped at 2400 µg. A total of 20 patients with COPD were then enrolled. All patients received a single-dose of V0162 1600 µg and of placebo in two alternating periods. In COPD patients, V0162 demonstrated a significant increase in FEV1 compared with placebo (148 ± 137 ml vs. 36 ± 151 ml, p = 0.003). This bronchodilatory effect was corroborated by a reduction in hyperinflation. There was a trend toward dyspnea relief (change in visual analog scale at 22 h, -15.1 ± 26.0 mm vs.- 5.3 ± 28.8 mm with placebo, p = 0.054). No serious adverse events (AEs) were reported. Most common AEs were productive and non-productive cough, dyspnea and pruritus. CONCLUSIONS: V0162 improved pulmonary function and tended to improve dyspnea in patients with COPD over more than 24 h. The slight plasmatic exposure observed might support the good safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01348555.

Clinical Evidence of the Benefits of Phytonutrients in Human Healthcare.

Phytonutrients comprise many different chemicals, including carotenoids, indoles, glucosinolates, organosulfur compounds, phytosterols, polyphenols, and saponins. This review focuses on the human healthcare benefits of seven phytochemical families and highlights the significant potential contribution of phytonutrients in the prevention and management of pathologies and symptoms in the field of family health. The structure and function of these phytochemical families and their dietary sources are presented, along with an overview of their potential activities across different health and therapeutic targets. This evaluation has enabled complementary effects of the different families of phytonutrients in the same area of health to be recognized.

Thrombin modifies growth, proliferation and apoptosis of human colon organoids: a protease-activated receptor 1- and protease-activated receptor 4-dependent mechanism.

BACKGROUND AND PURPOSE: Thrombin is massively released upon tissue damage associated with bleeding or chronic inflammation. The effects of this thrombin on tissue regrowth and repair has been scarcely addressed and only in cancer cell lines. Hence, the purpose of the present study was to determine thrombin's pharmacological effects on human intestinal epithelium growth, proliferation and apoptosis, using three-dimensional cultures of human colon organoids. EXPERIMENTAL APPROACH: Crypts were isolated from human colonic resections and cultured for 6 days, forming human colon organoids. Cultured organoids were exposed to 10 and 50 mU·mL-1 of thrombin, in the presence or not of protease-activated receptor (PAR) antagonists. Organoid morphology, metabolism, proliferation and apoptosis were followed. KEY RESULTS: Thrombin favoured organoid maturation leading to a decreased number of immature cystic structures and a concomitant increased number of larger structures releasing cell debris and apoptotic cells. The size of budding structures, metabolic activity and proliferation were significantly reduced in organoid cultures exposed to thrombin, while apoptosis was dramatically increased. Both PAR1 and PAR4 antagonists inhibited apoptosis regardless of thrombin doses. Thrombin-induced inhibition of proliferation and metabolic activity were reversed by PAR4 antagonist for thrombin's lowest dose and by PAR1 antagonist for thrombin's highest dose. CONCLUSIONS AND IMPLICATIONS: Overall, our data suggest that the presence of thrombin in the vicinity of human colon epithelial cells favours their maturation at the expense of their regenerative capacities. Our data point to thrombin and its two receptors PAR1 and PAR4 as potential molecular targets for epithelial repair therapies.