Pharmacokinetics and safety of repirinast tablets in healthy Chinese subjects

Repirinast is a new, synthetic, disodium cromoglycate-like antiallergic agent for oral administration in humans. This study evaluated the safety, tolerability and pharmacokinetics of repirinast tablets in healthy Chinese volunteers. This was a phase I, open-label, randomized, single- and multiple-dose study. Subjects were assigned to receive a single dose of repirinast tablet at either 150, 300, or 450 mg, or multiple doses of 150 mg twice daily for 5 days. Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of active metabolite MY-1250 (deesterified repirinast) were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 0.75 hour, and the mean t1/2 was approximately 16.21 hours. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 150 to 450 mg. In the multiple-dose study, the steady-state was reached within 3 days with no accumulation. Repirinast tablet was well tolerated in healthy Chinese subjects

Pharmacokinetics and safety of repirinast tablets in healthy Chinese subjects

ABSTRACT Repirinast is a new, synthetic, disodium cromoglycate-like antiallergic agent for oral administration in humans. This study evaluated the safety, tolerability and pharmacokinetics of repirinast tablets in healthy Chinese volunteers. This was a phase I, open-label, randomized, single- and multiple-dose study. Subjects were assigned to receive a single dose of repirinast tablet at either 150, 300, or 450 mg, or multiple doses of 150 mg twice daily for 5 days. Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of active metabolite MY-1250 (deesterified repirinast) were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 0.75 hour, and the mean t1/2 was approximately 16.21 hours. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 150 to 450 mg. In the multiple-dose study, the steady-state was reached within 3 days with no accumulation. Repirinast tablet was well tolerated in healthy Chinese subjects

The efficacy of platelet rich plasma on anterior cruciate ligament reconstruction: a systematic review and meta-analysis

Anterior cruciate ligament (ACL) rupture is a common musculoskeletal injury, most frequently affecting young and physically active patients. Platelet-rich plasma (PRP) has been widely used in ACL reconstruction to augment the graft healing. However, high-level studies addressing its clinical efficacy could not reach a consensus. In this study, we assess the efficacy of PRP on pain relief, functional improvement along with radiological changes in patients who underwent ACL reconstruction. We performed comprehensive literature search and included 17 RCTs containing 970 participants who underwent ACL reconstruction. The combined data showed significant difference between PRP and control with regard to VAS score (MD: −1.12, 95% CI −1.92, −0.31; P = .007), subjective IKDC score (MD: 6.08, 95% CI 4.39, 7.77; P < .00001) and Lysholm score (MD: 8.49, 95% CI 1.63, 15.36; P = .02) by postoperative 6 months, but only pain reduction was deemed clinically important. At the end of one year’s follow-up, no clinically meaningful improvement in VAS (MD: −0.47, P = .04), subjective IKDC score (MD: 3.99, P = .03), Lysholm score (MD: 2.30, P = .32), objective IKDC score (RR: 1.03, P = .09) and knee joint laxity (MD: 0.17, P = .28) was seen. In terms of radiological findings, about one-third of the studies favored PRP to facilitate the graft healing, improve the harvest site morbidity and prevent tunnel widening. In summary, moderate quality of evidence suggested that PRP could provide short-term but not long-term clinically important pain reduction

Rupatadine Protects against Pulmonary Fibrosis by Attenuating PAF-Mediated Senescence in Rodents

<div><p>A similar immune response is implicated in the pathogenesis of pulmonary fibrosis and allergic disorders. We investigated the potential therapeutic efficacy and mechanism of rupatadine, a dual antagonist of histamine and platelet-activation factor (PAF), in bleomycin- (BLM-) and silica-induced pulmonary fibrosis. The indicated dosages of rupatadine were administered in rodents with bleomycin or silica-induced pulmonary fibrosis. The tissue injury, fibrosis, inflammatory cells and cytokines, and lung function were examined to evaluate the therapeutic efficacy of rupatadine. The anti-fibrosis effect of rupatadine was compared with an H1 or PAF receptor antagonist, and efforts were made to reveal rupatadine’s anti-fibrotic mechanism. Rupatadine promoted the resolution of pulmonary inflammation and fibrosis in a dose-dependent manner, as indicated by the reductions in inflammation score, collagen deposition and epithelial-mesenchymal transformation, and infiltration or expression of inflammatory cells or cytokines in the fibrotic lung tissue. Thus, rupatadine treatment improved the declined lung function and significantly decreased animal death. Moreover, rupatadine was able not only to attenuate silica-induced silicosis but also to produce a superior therapeutic efficacy compared to pirfenidone, histamine H1 antagonist loratadine, or PAF antagonist CV-3988. The anti-fibrotic action of rupatadine might relate to its attenuation of BLM- or PAF-induced premature senescence because rupatadine treatment protected against the <i>in vivo</i> and <i>in vitro</i> activation of the p53/p21-dependent senescence pathway. Our studies indicate that rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF-mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.</p> </div

Rupatadine maintains autophagic flux in fibrotic lung tissue.

<p>(<b>A</b>) Rupatadine (6.0 mg/kg per day) regulated the expression or activity of autophagy-related molecules in the fibrotic lung tissue. Lung tissue extract was prepared for western blotting. The data are representative immune blots and expressed as the mean ± SEM of 6 mice per group. (<b>B</b>) Rupatadine (6.0 mg/kg per day) maintained the autophagic flux in the fibrotic lung tissue. Representative images of lung sections were acquired by confocal microscopy for LC3-II (green)/ LAMP1 (red). Scale bar in images = 200 μm. The data are representative images of 3 assays with identical results. ^#<i>P</i><0.05, ^{# #}<i>P</i><0.01 vs. Sham group; ^*<i>P</i><0.05, ^**<i>P</i><0.01 vs. BLM treated group.</p

Rupatadine promotes the resolution of inflammatory responses.

<p>(<b>A</b>) BALF was collected on day 28 after BLM administration, and the counts of total WBC and classified cells were evaluated by differential counting. The data are expressed as the mean ± SEM of 8 mice per group. (<i>B</i> and <i>C</i>) Rupatadine decreased the population of lung-infiltrating mast cells and stabilized their activity in the fibrotic lung tissue. The density of mast cells in examined lung sections was detected by staining with 0.05% (w/v) toluidine blue (shown by arrows). The data are representative images of 3 assays with similar results. The mast cells (shown by arrow) were counted in 15 fields at 400x of each mouse. The data are representative images and are summarized as the mean ± SEM of 8 mice per group. Scale bar in images = 200 μm(B). The expression of MCP-7, a specific protease secreted by mast cell degranulation, was detected by Western blotting (C). The data are representative immune blots and summarized as the mean ± SEM of 8 mice per group. (<b>D</b> and <b>E</b>) Rupatadine (6.0 mg/kg per day) regulated the infiltration and polarization of macrophages in BALF in the fibrotic mice. Images of BALF cells on glass coverslips were acquired by confocal microscopy for MAC-3 (red) iNOS (green in top) and Arg-1 (green in bottom). The data are representative images of 3 assays. Scale bar in images = 10 μm(D). M1 and M2 cells on the sections were analyzed by Image-Pro Plus software and expressed as the mean ± SEM of 6 mice per group (E). ^#<i>P</i><0.05, ^{# #}<i>P</i><0.01 vs. Sham group; ^*<i>P</i><0.05, ^**<i>P</i><0.01 vs. BLM treated group.</p

Rupatadine reduces enhanced lung density and improves lung functions in fibrotic mice.

<p>(<b>A</b>–<b>C</b>) Rupatadine treatment reduced the BLM-induced lung density shown by micro-CT. Representative micro-CT of main pulmonary lesions of Sham- (A, left), BLM instilled- (A, middle) and rupatadine-treated mice (6.0 mg/kg per day) (A, right) were shown at different slices. Quantification of lung parenchyma density was measured in upper, central and lower pulmonary regions excluding the hilum and bronchi. Scale bar in images = 1 cm. The data are expressed as the mean Hounsfield units (HU) ± SEM of 8 mice per group (B). Rupatadine (6.0 mg/kg per day) reduced parenchymal loss in the fibrotic mice (C). (<b>D</b>) Rupatadine (6.0 mg/kg per day) improved lung functions in the fibrotic mice. Mice were anesthetized with 50 mg/kg i.p. pentobarbital and placed on the flexivent system at the indicated times after bleomycin administration. Mice were mechanically ventilated with a tidal volume of 10 ml/kg and a respiratory rate of 150 breaths/min. The parameters of lung function were calculated by measuring total lung capacity, Snapshot, Quickprime-3, and pressure-volume loops. All perturbations were performed until three acceptable measurements with a coefficient of determination (COD) ≥ 0.9 were recorded for each individual subject. The data are expressed as the mean ± SEM of 6 mice per group. ^#<i>P</i><0.05, ^{# #}<i>P</i><0.01 vs. Sham group; ^*<i>P</i><0.05, ^**<i>P</i><0.01 vs. BLM treated group.</p

Rupatadine attenuates BLM-induced pulmonary fibrosis.

<p>The mice were intragastrically administered with solvent alone (sham group) or rupatadine at 1.5, 3.0, or 6.0 mg/kg per day from day 10 to 28 after BLM administration (5 U/kg). On day 28, mice were sacrificed and a lung was obtained for histological analysis and other studies. (<b>A</b>–<b>D</b>) Rupatadine attenuated pulmonary fibrosis and inflammation. Representative H&E staining data are shown (A, top), and the expression of α-SMA in fibrotic lungs. The lung sections were stained with an anti-α-SMA antibody for immunohistochemistry analysis (A, bottom). The IOD of each section was analyzed by Image-Pro Plus image analysis software (D) (n=10 per group). Inflammatory score was evaluated by a professional pathologist who was blind to the animal groups (B) (n=15 per group). Rupatadine treatment reduced the lung index in a dose-dependent manner (C) (n=10 per group). (<b>E</b>–<b>G</b>) Rupatadine decreased collagen deposition in the lungs. The lung tissue sections were stained with Sirius Red (SR) (normal light and polarized light) to indicate the collagen deposition (E and F). Additionally, rupatadine decreased hydroxyproline contents in fibrotic mice (<b>G</b>). Scale bar in images = 200 μm. The representative images in A and E were obtained from animals treated with rupatadine of 6.0 mg/kg per day. Data are expressed as the mean ± SEM of 8 mice per group. Rupatadine treatment inhibited the fibrosis-associated molecules in the fibrotic lung tissue (<b>H</b>). Western blot analysis was performed on lung lysates and detected the expression of α-SMA, E-cadherin and collagen-I in lung tissue. Data were expressed as folds of the sham group ± SEM of 8 mice per group. Rupatadine decreased animal death in BLM-injured mice (<b>I</b>). The cumulative survival rates of mice were analyzed by the Kaplan-Meier method (n=40 per group which were at the start of the experiment). ^#<i>P</i><0.05, ^{# #}<i>P</i><0.01 vs. Sham group; ^*<i>P</i><0.05, ^**<i>P</i><0.01 vs. BLM treated group.</p