Ladarixin, an inhibitor of the interleukin-8 receptors CXCR1 and CXCR2, in new-onset type 1 diabetes: A multicentre, randomized, double-blind, placebo-controlled trial.

Aim: To evaluate the ability of ladarixin (LDX, 400 mg twice-daily for three cycles of 14 days on/14 days off), an inhibitor of the CXCR1/2 chemokine receptors, to maintain C-peptide production in adult patients with newly diagnosed type 1 diabetes.

Materials And Methods: A double-blind, randomized (2:1), placebo-controlled study was conducted in 45 males and 31 females (aged 18-46 years) within 100 days of the first insulin administration. The primary endpoint was the area under the curve (AUC) for C-peptide in response to a 2-hour mixed meal tolerance test (AUC ) at week 13 ± 1.

Targeting CXCR1/2 in the first multicenter, double-blinded, randomized trial in autologous islet transplant recipients.

Several cytokines and chemokines are elevated after islet infusion in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT), including CXCL8 (also known as interleukin-8), leading to islet loss. We investigated whether use of reparixin for blockade of the CXCL8 pathway would improve islet engraftment and insulin independence after TPIAT. Adults without diabetes scheduled for TPIAT at nine academic centers were randomized to a continuous infusion of reparixin or placebo (double-blinded) for 7 days in the peri-transplant period.

Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes.

Objective: Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients.

Research Design And Methods: A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant.

CXCR1/2 inhibition blocks and reverses type 1 diabetes in mice.

Chemokines and their receptors have been associated with or implicated in the pathogenesis of type 1 diabetes (T1D), but the identification of a single specific chemokine/receptor pathway that may constitute a suitable target for the development of therapeutic interventions is still lacking. Here, we used multiple low-dose (MLD) streptozotocin (STZ) injections and the NOD mouse model to investigate the potency of CXCR1/2 inhibition to prevent inflammation- and autoimmunity-mediated damage of pancreatic islets. Reparixin and ladarixin, noncompetitive allosteric inhibitors, were used to pharmacologically blockade CXCR1/2.

CXCR1/2 inhibition enhances pancreatic islet survival after transplantation.

Although long considered a promising treatment option for type 1 diabetes, pancreatic islet cell transformation has been hindered by immune system rejection of engrafted tissue. The identification of pathways that regulate post-transplant detrimental inflammatory events would improve management and outcome of transplanted patients. Here, we found that CXCR1/2 chemokine receptors and their ligands are crucial negative determinants for islet survival after transplantation.

S-CMC-Lys-dependent stimulation of electrogenic glutathione secretion by human respiratory epithelium.

Glutathione (GSH) is one of the most important defense mechanisms against oxidative stress in the respiratory epithelial lining fluid. Considering that GSH secretion in respiratory cells has been postulated to be at least partially electrogenic, and that the mucoregulator S-carbocysteine lysine salt monohydrate (S-CMC-Lys) can cause an activation of epithelial Cl(-) conductance, the purpose of this study was to verify whether S-CMC-Lys is able to stimulate GSH secretion. Experiments have been performed by patch-clamp technique, by high-performance liquid chromatography (HPLC) assay, and by Western blot analysis on cultured lines of human respiratory cells (WI-26VA4 and CFT1-C2).

Levodropropizine does not affect P0.1 and breathing pattern in healthy volunteers and patients with chronic respiratory impairment.

To evaluate whether the peripherally acting antitussive levodropropizine could affect the respiratory drive and the breathing pattern, we performed a double-blind, randomised, cross-over trial in 12 healthy volunteers and 12 patients with chronic respiratory impairment associated with chronic obstructive pulmonary disease. Levodropropizine 6% drops (at the recommended dose for adults) or placebo were administered orally t.i.

Protective effect of ketoprofen lysine salt on interleukin-1beta and bradykinin induced inflammatory changes in hamster cheek pouch microcirculation.

Objective: The purpose of this study was to assess the efficacy of topically applied ketoprofen lysine salt (KLS), a cyclooxygenase inhibitor, against the inflammatory changes induced by interleukin-1beta (IL-1beta) and bradykinin (BK) in hamster cheek pouch microcirculation. In addition, we characterised the pharmacological regulation of IL-1beta activity in this model.

Materials And Methods: Male Syrian hamsters were used.

Antioxidant activity of carbocysteine lysine salt monohydrate.

Background: Reactive oxygen radicals are involved in many respiratory diseases, including chronic obstructive pulmonary disease (COPD). Carbocysteine lysine salt monohydrate (CLS) is a mucoactive drug effective in the treatment of bronchopulmonary diseases characterized by mucus alterations, including COPD. In the present study, the antioxidant activity of CLS was studied in vitro in three different oxygen radical producing systems, i.

Efficacy and safety of levodropropizine and dihydrocodeine on nonproductive cough in primary and metastatic lung cancer.

Nonproductive cough is a frequent and distressing symptom in patients with lung cancer, and it is not even relieved by palliative chemotherapy. A double-blind, randomized clinical trial regarding the treatment of nonproductive cough was performed in 140 adults with primary lung cancer or metastatic cancer of the lungs. The therapeutic efficacy and the tolerability of a 7-day treatment with levodropropizine drops (75 mg t.

S-carbocysteine-lysine salt monohydrate and cAMP cause non-additive activation of the cystic fibrosis transmembrane regulator channel in human respiratory epithelium.

S-Carbocysteine-lysine salt monohydrate (S-CMC-Lys) has been shown to open a Cl- channel in the trachea, thus aiding fluid secretion. The aim of this study was to characterize the channel and the action mechanism on a culture line of human respiratory epithelial cells. The patch-clamp technique (in cell-attached or inside-out configuration) and conventional micro-electrodes were used.

Efficacy and tolerability of levodropropizine in adult patients with non-productive cough. Comparison with dextromethorphan.

The results of a double-blind, randomized clinical trial involving 209 adult patients of either sex with moderate non-productive cough are reported. The therapeutic efficacy and the tolerability of levodropropizine syrup (60 mg t.i.

Effect of frusemide on Cl- channel in rat peritoneal mast cells.

Frusemide can be used as an antiasthma drug and appears to inhibit the release (conditioned by activation of Cl- channels) of mast cell proinflammatory mediators. We studied the cause of the effects of frusemide, checking its action on Cl- channels. The patch-clamp technique was used to study single-channel currents, and differences in electrical potential of the cellular membrane of rat peritoneal mast cells were measured.

Protective activity of ketoprofen lysine salt against the pulmonary effects induced by bradykinin in guinea-pigs.

We investigated the capacity of ketoprofen lysine salt (KLS) to counteract the pulmonary effects of some mediators of airway inflammation. The protective effect of KLS and its R-isomer against bradykinin (BK) induced plasma extravasation in the airways and bronchoconstriction was evaluated in anaesthetized guinea-pigs, in parallel with the capacity of KLS to inhibit the production of thromboxane A2 (TXA2). Moreover, we studied the ability of KLS to modulate leukotriene C4 (LTC4) and acetylcholine (ACH) induced bronchoconstriction and the associated production of TXA2.

Effects of levodropropizine on vagal afferent C-fibres in the cat.

1. Levodropropizine (LVDP) is an effective antitussive drug. Its effects on single-unit discharge of vagal afferent C-fibres were tested in anaesthetized cats to assess whether an inhibition of vagal C-fibres is involved in its antitussive properties.

Effectiveness of carbocysteine lysine salt monohydrate on models of airway inflammation and hyperresponsiveness.

We investigated the possible effects of the mucoactive drug Carbocysteine lysine salt monohydrate (CLS.H2O) on experimentally-induced airway inflammation and hyperresponsiveness. CLS.

Effects of a new foam formulation of ketoprofen lysine salt in experimental models of inflammation and hyperalgesia.

The anti-inflammatory and analgesic profile of a new topical foam formulation of ketoprofen lysine salt (CAS 57469-78-0, Artrosilene Schiuma, KLS-foam) was characterized in comparison with marketed gel formulations containing KLS (KLS-gel) or diclofenac diethylammonium salt (DCF-gel). KLS-foam dose-dependently inhibited oedema formation and hyperalgesia induced by subplantar injection of carrageenan or substance P, being more potent than KLS-gel. At equieffective anti-inflammatory doses, KLS-foam provided a more pronounced analgesic effect than DCF-gel.

Effect of S-carboxymethylcysteine lysine salt on mucociliary clearance in rabbits with secretory cell metaplasia.

A single intratracheal instillation of porcine pancreatic elastase (PPE, 100 U/Kg) induces in rabbits bronchial secretory cell metaplasia as well as emphysematous changes. The mucus hypersecretion and the marked reduction of ciliated cells matched by a high percentage of atypical cilia are responsible for the delayed mucociliary clearance in this model. S-Carboxymethylcysteine lysine salt (SCMC-LYS, 0.

Stimulation of Cl- secretion by the mucoactive drug S-carboxymethylcysteine-lysine salt in the isolated rabbit trachea.

Ion transport by the airway epithelium contributes to the regulation of the quantity and composition of respiratory tract fluid, thereby affecting mucociliary clearance. We have investigated the effect of the mucoactive drug S-carboxymethylcysteine-lysine salt (S-CMC-Lys) on the transepithelial bioelectric properties of isolated rabbit trachea. Transepithelial potential difference (Vms), short-circuit current (Isc) and resistance (R) were measured in the isolated rabbit trachea mounted between flux half-chambers, in the presence and in the absence of S-CMC-Lys (100 microM), added to the mucosal or submucosal chamber.

Effect of 3'-hydroxyfarrerol on airway hyperreactivity induced by acute cigarette smoke exposure in guinea pigs.

The (+/-)-3'-hydroxyfarrerol (IdB 1031) is a new drug endowed with an interesting mucokinetic activity. In this study the effectiveness of IdB 1031 has been verified in a model of airway hyperreactivity and lung inflammation induced in anaesthetized guinea pig by active cigarette smoke exposure. IdB 1031 (500 mg/kg per os) completely inhibited the capacity of cigarette smoke to induce airway hyperreactivity.

Effect of a mucoactive compound (CO 1408) on airway hyperreactivity and inflammation induced by passive cigarette smoke exposure in guinea-pigs.

Environmental exposure to tobacco smoke contributes to the onset of several lung diseases, e.g. chronic bronchitis and asthma, including an increase in airway reactivity.

Levodropropizine reduces capsaicin- and substance P-induced plasma extravasation in the rat trachea.

We investigated the effect of the non-opioid, peripherally acting antitussive agent levodropropizine to reduce neurogenic plasma extravasation in the rat trachea. Levodropropizine (10, 50 and 200 mg/kg) reduced in a dose-dependent manner the extravasation of Evans blue dye evoked by capsaicin. Levodropropizine inhibited also substance P-evoked extravasation, whereas it did not affect the extravasation evoked by platelet activating factor.

Effectiveness of levodropropizine against cigarette smoke-induced airway hyperreactivity: possible mechanism.

We verified the possible effect of the new antitussive drug levodropropizine on airway hyperreactivity and lung inflammation induced by cigarette smoke exposure in anaesthetized guinea-pigs. Levodropropizine, administered by aerosol at 25 mg/ml for 30 s completely prevented smoke induced airway hyperreactivity. The protective effect was early in onset (3 min) and lasted up to 30 min.

Changes in airway reactivity to exogenous and endogenous acetylcholine and substance P after anaphylactic bronchoconstriction in anaesthetized guinea-pigs.

1. In anaesthetized, actively sensitized guinea-pigs, the anaphylactic shock induced by antigen aerosol challenge (5 s; 50 mg ml-1) was followed by increase in airway reactivity to both acetylcholine and substance P. In particular dose-response curves to acetylcholine (3-1000 micrograms kg-1 i.

Nedocromil sodium prevents airway hyperreactivity induced by cigarette smoke in anaesthetized guinea-pigs.

Increased airway reactivity and influx of inflammatory cells into the airways have been demonstrated both in smokers and after smoke exposure in animal studies. We investigated the ability of nedocromil sodium and hydrocortisone to protect from the pathological alterations induced by direct cigarette smoke exposure in anaesthetized guinea-pigs. Active inhalation of cigarette smoke (15 s/min for 10 min) induced airway hyperreactivity, as shown by the enhanced bronchoconstrictor effect of histamine and was associated with an increase in total cells, macrophages and eosinophils in the BAL fluid.