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Siraitia grosvenorii is an edible fruit with the functions of relieving heat and relieving cough. Here, we found that mogroside-rich extract (MGE) from Siraitia grosvenorii can prevent heat stress-induced intestinal damage by alleviating oxidative stress and inflammation.

Oxidative stress can induce lung damage and aggravate airway inflammation in asthma. Previously, we reported that rosmarinic acid (RA) exerted strong anti-inflammatory effects in a mouse allergic asthma model. Therefore, we hypothesized that RA might also have antioxidative effects in a superimposed asthma mouse model with oxidative lung damage challenged with ovalbumin (Ova) and hydrogen peroxide (H2O2). We evaluated the antioxidative and anti-asthmatic activity of RA and explored its possible mechanisms of action. Mice sensitized to Ova and challenged with Ova and H2O2 were treated with RA 1 h after challenge. RA treatment greatly diminished the number of inflammatory cells; decreased IL-4, IL-5, and IL-13 production; increased IFN-γ secretion; significantly downregulated ROS production; and markedly upregulated the activities of SOD, GPx, and CAT. Furthermore, RA treatment resulted in a significant increase in the expression of Cu/Zn SOD and a notable reduction in NOX-2 and NOX-4 expression in lung tissues. These findings suggest that RA may effectively alleviate oxidative lung damage and airway inflammation in asthma.

This study was designed to develop orally disintegrating/sustained-release praziquantel (PZQ) tablets using the hot-melt extrusion (HME) technique and direct compression, and subsequently evaluate their release in in vitro and in vivo pharmacokinetics. For the extrusion process, hypromellose acetate succinate (HPMCAS)-LG was the carrier of pure PZQ, with a standard screw configuration used at an extrusion temperature of 140 °C and a screw rotation speed of 100 rpm. Differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD) and Fourier-transform infrared spectroscopy (FTIR) were performed to characterize the extrudate. Orally disintegrating/sustained-release praziquantel tablets (PZQ ODSRTs) were prepared by direct compression after appropriate excipients were blended with the extrudate. The release amount was 5.10% in pH 1.0 hydrochloric acid at 2 h and over 90% in phosphoric acid buffer at 45 min, indicating the enteric-coating character of PZQ ODSRTs. Compared with the pharmacokinetics of marketed PZQ tablets (Aipuruike®) in dogs, the times to peak (Tmax), elimination half-life (t1/2λ) and mean residence time (MRT) were extended in PZQ ODSRTs, and the relative bioavailability of PZQ ODSRTs was up to 184.48% of that of Aipuruike®. This study suggested that PZQ ODSRTs may have potential for the clinical treatment of parasitosis.

Flunixin meglumine (FM) is a nonsteroidal anti-inflammatory drug limited by irritation of the respiratory tract and mucosa in veterinary tissue. This study aimed to develop a taste-masked FM solid dispersion (SD) by hot-melt extrusion (HME) and formulate an orally disintegrating tablet (ODT) with selected excipients by direct compression. Eudragit® E PO was chosen as the matrix, and HME parameters were optimized: extrusion temperature, 135℃; screw speed, 100 rpm; and drug loading, 20%. Characterization techniques proved that FM was rendered amorphous in the HME extrudate. In vitro dissolution studies showed that FM SD released significantly slower than the corresponding physical mixture in artificial saliva. Excipients were selected based on compression formability, disintegration, and solubility. A D-optimal mixture design was used to optimize the composition: 25% FM SD, 18.75% microcrystalline cellulose, 52.5% mannitol, 3.75% low-substituted hydroxypropyl cellulose, and 1% magnesium stearate. Taste-masked FM ODT had a tensile strength of 0.7 ± 0.01 MPa and a disintegration time of 17.6 ± 0.1 s. E-tongue and E-nose analysis showed that FM ODT had a better taste-masked effect than commercial granules. Finally, a pharmacokinetic study proved that the main pharmacokinetic parameters of FM ODT were not significantly different from those of commercial granules, which indicated that these formulations had similar pharmacokinetic behaviours in beagles.

In view of complex optimization problems with high nonlinearity and multiple extremums, harmony search algorithm has problems of slow convergence speed, being easy to be stalled and difficult to combine global search with local search. Therefore, a global competitive harmonic search algorithm based on stochastic attraction is proposed. Firstly, by introducing the stochastic attraction model to adjust the harmonic vector, the harmonic search algorithm was greatly improved and prone to fall into the local optimum. Secondly, the competitive search strategy was made to generate two harmony vectors for each iteration and make competitive selection. The adaptive global adjustment and local search strategy were designed to effectively balance the global and local search capabilities of the algorithm. The typical test function was used to test the algorithm. The experimental results show that the algorithm has high precision and the ability to find the global optimum compared with the existing algorithms. The overall accuracy is increased by more than 50%.

Tilmicosin (TMS) is a macrocyclic antibiotic specially used in veterinary clinics, but its extreme bitterness limits its use. This study aimed to obtain a taste-masked formulation of TMS by hot melt extrusion (HME) technology and to investigate the formulation’s characterization, stability, and effects in vitro/in vivo. Eudragit® E PO was selected as the carrier, and TMS dissolution in artificial saliva was used as a reference. The HME parameters were optimized via an orthogonal design. The optimized results were as follows: 135 ℃ extrusion temperature, 100 rpm screw speed and 30 % drug load. The masking efficiency of the formulation was evaluated by both simulated oral drug release in vitro and electronic tongue tests. The release of the taste-masked formulation in artificial saliva medium was significantly reduced within 60 s (less than 2%), while the release in 0.1 M HCl buffer was fast (more than 80 %) within 30 min. As suggested by the results of the electronic tongue, the taste-masked formulation had a better taste-masked effect than the commercial premix and the commercial enteric granules. Finally, a pharmacokinetic study was performed. Analysis of variance demonstrated that the pharmacokinetic behavior of the TMS taste-masked formulation was similar to that of the commercial premix, while the absorption effect was better than that of the commercially available enteric granules. This research indicates that the taste-masked formulation has the potential for future commercialization.

The objective of this work was to manufacture an enteric formulation of florfenicol (FF) using hot-melt extrusion (HME) technology and to evaluate its in vitro dissolution and in vivo pharmacokinetics. For the HME process, hypromellose acetate succinate LG (HPMCAS-LG) was the enteric polymer mixed with FF, and the two components were extruded with a standard screw configuration at a speed of 50 rpm. Differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FT-IR) were performed to characterize the HME extrudate. The release percentage of the enteric formulation in the acidic stage was 80%. Pharmacokinetic evaluations in swine revealed that the enteric formulation had a longer t1/2λ and MRT than commercially available FF powder (FULAIKA® ), indicating that the novel formulation exhibited enteric and sustained release properties. Compared with the commercial product, the relative bioavailability of the enteric formulation reached up to 117.2%. This study suggests that this formulation may have potential for future commercialization.

Rosmarinic acid (RA) is an active component of a traditional Chinese herbal medicine. Previously, we reported that RA exerted a strong anti-inflammatory effect in a mouse acute lung injury model. Therefore, we hypothesized that RA might also have potential therapeutic effects in a murine model of asthma. In this study, we aimed to evaluate the anti-asthmatic activity of RA and explored its possible molecular mechanisms of action. Female BALB/c mice that had been sensitized to and challenged with ovalbumin (Ova) were treated with RA (20mg/kg) 1h after challenge. The results showed that RA greatly diminished the number of inflammatory cells and the production of Th2 cytokines in the bronchoalveolar lavage fluid (BALF); significantly reduced the secretion of total IgE, Ova-specific IgE, and eotaxin; and markedly ameliorated airway hyperresponsiveness (AHR) compared with Ova-induced mice. Histological studies further revealed that RA substantially decreased inflammatory cells infiltration and mucus hypersecretion compared with Ova-induced mice. Moreover, our results suggested that the protective effects of RA were mediated by the inhibition of JNK and p38 MAPK phosphorylation and nuclear factor-κB (NF-κB) activation. Furthermore, RA treatment resulted in a significant reduction in the mRNA expression of AMCase, CCL11, CCR3, Ym2 and E-selectin in lung tissue. These findings suggest that RA may effectively delay the development of airway inflammation and could thus be used as a therapy for allergic asthma.

A new oil suspension containing 0.15% ivermectin and 15% praziquantel for intramuscular injection was developed, and corresponding pharmacokinetics studies were conducted in swine. The combination product is a white- to cream-colored oil suspension and its physical properties such as settling volume ratio, redispersibility, syringeability and flowability are well consistent with the Technical Standards by the Ministry of Agriculture of the People's Republic of China. The pharmacokinetic study consists of two parts. First, the experiments were carried out to compare the pharmacokinetic parameters of the combination product and those same products with praziquantel or ivermectin removed merely. The results showed that no significant change in the major pharmacokinetic parameters (t(1/2z), T(max), C(max), AUC(INF), TimeDur) was observed when either of the component was removed from the combination product, indicating that ivermectin and praziquantel do not interfere with each other when being used together. Second, the pharmacokinetics of the combination product were compared with those of their respective single product. The results showed that the C(max) (15.94 ng/mL) of ivermectin in combination product was 9.01 times higher than the single product, while the AUC(INF) (1925.61 ng h/mL) was 6.02 times higher. Meanwhile, the C(max) (1.48 μg/mL), AUC(INF) (17.08μgh/mL), t(1/2z) (20.25 h), TimeDur3 (42.01 h) and TimeDur4 (16.60 h) of praziquantel in combination product were improved with a factor of 5.48, 13.66, 8.58, 10.10 and 7.31 times when compared with the single product, respectively. Therefore, the efficacy of the combination product was significantly prolonged, especially for praziquantel, so that comprehensive efficacy of controlling parasites sensitive to ivermectin and praziquantel can be achieved with one-single use of it.

A new oil suspension containing 0.10% ivermectin (IVM) and 15% praziquantel (PZQ) (Tivm+pzq) for intramuscular injection was developed for sheep, and its pharmacokinetics was investigated in sheep. The quality of the new product met the technical standards set by the Ministry of Agriculture of the People's Republic of China. In pharmacokinetics, the commercially available single-component products approved by the Chinese Ministry of Agriculture and widely used in the livestock industry in China were selected as reference products (Rivm and Rpzq). The results showed that all of the IVM pharmacokinetic parameters of Tivm+pzq were similar to those of the reference. However, after adminstration of Tivm+pzq, mean residence time (MRT) and plasma elimination half-life (t1/2z) were 20.36h and 11.65h, which were 2.61 and 3.22 times longer than those of Rpzq (7.81h and 3.62h). In summary, the MRT and t1/2z of PZQ in Tivm+pzq were prolonged and IVM pharmacokinetic parameters were similar to commercial product, therefore the new injection may be an alternative choice for sheep to control parasites sensitive to IVM and PZQ.

A sensitive and robust high-performance liquid chromatographic method with fluorescence detection (HPLC-FLD) was developed for the determination of gentamicin (GEN) residues in swine tissues. The limit of quantification (LOQ) of the method was 50 ng/g for muscle and 100 ng/g for liver and kidney. Mean recoveries at all fortification levels ranged from 82.34 to 93.20% with coefficient of variation (CV) below 5.39%. Residue depletion study of GEN in swine was performed after intramuscular injections twice daily at a dose of 4 mg/kg of bw with 12 h intervals for 5 consecutive days. The concentrations of GEN were determined in injection site, muscle, liver, and kidney by the HPLC-FLD method. The highest GEN concentration was measured in kidney, indicating that kidney was the primary target tissue for GEN residue. GEN concentrations in all examined tissues were below the maximum residue limit (MRL) recommended by the European Union (EU) at 50 days post-treatment.

Rosmarinic acid (RA) has numerous pharmacologic effects, including anti-oxidant, anti-inflammatory, and analgesic effects. This study aimed to evaluate the preventive activity of RA in a murine model of asthma and to investigate its possible molecular mechanisms. Female BALB/c mice sensitized and challenged with ovalbumin (Ova) were pretreated with RA (5, 10 or 20 mg/kg) at 1 h before Ova challenge. The results demonstrated that RA markedly inhibited increases in inflammatory cells and Th2 cytokines in the bronchoalveolar lavage fluid (BALF), significantly reduced the total IgE and Ova-specific IgE concentrations, and greatly ameliorated airway hyperresponsiveness (AHR) compared with the control Ova-induced mice. Histological analyses showed that RA substantially decreased the number of inflammatory cells and mucus hypersecretion in the airway. In addition, our results suggested that the protective effects of RA might be mediated by the suppression of ERK, JNK and p38 phosphorylation and activation of nuclear factor-κB (NF-κB). Furthermore, RA pretreatment resulted in a noticeable reduction in AMCase, CCL11, CCR3, Ym2 and E-selectin mRNA expression in lung tissues. These findings suggest that RA may effectively delay the progression of airway inflammation.

Rosmarinic acid (RA), a polyphenolic phytochemical, is a natural prolyl oligopeptidase inhibitor. In the present study, we found that RA exerted potent anti-inflammatory effects in in vivo models of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Mice were pretreated with RA one hour before challenge with a dose of 0.5 mg/kg LPS. Twenty-four hours after LPS was given, bronchoalveolar lavage fluid (BALF) was obtained to measure pro-inflammatory mediator and total cell counts. RA significantly decreased the production of LPS-induced TNF-a, IL-6, and IL-1β compare with the LPS group. When pretreated with RA (5, 10, or 20 mg/kg) the lung wet-to-dry weight (W/D) ratio of the lung tissue and the number of total cells, neutrophils and macrophages in the BALF were decreased significantly. Furthermore, RA may enhance oxidase dimutase (SOD) activity during the inflammatory response to LPS-induced ALI. And we further demonstrated that RA exerts anti-inflammation effect in vivo models of ALI through suppresses ERK/MAPK signaling in a dose dependent manner. These studies have important implications for RA administration as a potential treatment for ALI.

Ginkgolide B is an anti-inflammatory extract of Ginkgo biloba and has been used therapeutically. It is a known inhibitor of platelet activating factor (PAF), which is important in the pathogenesis of asthma. Here, a non-infectious mouse model of asthma is used to evaluate the anti-inflammatory capacity of ginkgolide B (GKB) and characterize the interaction of GKB with the mitogen activated protein kinase (MAPK) pathway. BALB/c mice that were sensitized and challenged to ovalbumin (OVA) were treated with GKB (40 mg/kg) one hour before they were challenged with OVA. Our study demonstrated that GKB may effectively inhibit the increase of T-helper 2 cytokines, such as interleukin (IL)-5 and IL-13 in bronchoalveolar lavage fluid (BALF). Furthermore, the eosinophil count in BALF significantly decreased after treatment of GKB when compared with the OVA-challenged group. Histological studies demonstrated that GKB substantially inhibited OVA-induced eosinophilia in lung tissue and mucus hyper-secretion by goblet cells in the airway. These results suggest that ginkgolide B may be useful for the treatment of asthma and its efficacy is related to suppression of extracellular regulating kinase/MAPK pathway.

Salidroside, a major component of Rhodiola rosea L., was evaluated for its adjuvant effects on the immune responses in mice by ovalbumin (OVA) stimulation. BALB/c mice were immunized subcutaneously with OVA 100 μg or OVA 100 μg dissolved in saline containing alum (100 μg) or salidroside (12.5, 25, or 50 μg) on Days 1 and 15. Two weeks later (Day 28), blood samples were collected to analyze OVA-specific IgG, IgG1, and IgG2b antibodies. Meanwhile, splenocytes were harvested to assess lymphocyte proliferation, cytokines (IL-2, IL-4, and IFN-γ) production, and CD4(+), CD8(+) lymphocyte subsets. The results indicated that co-administration of salidroside with OVA significantly enhanced the ConA-, LPS-, and OVA-induced splenocyte proliferation, produced more IL-2, IL-4, IFN-γ, and IgG, IgG1, and IgG2b antibody levels, and increased the percentage of CD4(+), CD8(+) lymphocyte subsets than OVA alone. Thus, salidroside possess immunological adjuvant activity by regulating humoral and cellular immune responses in mice.