The Effectiveness of the Bacteria Derived Extremolyte Ectoine for the Treatment of Allergic Rhinitis.

Nonpharmacological therapies with a good tolerability and safety profile are of interest to many patients with allergic rhinitis, as a relevant proportion of them have reservations about guideline-concordant pharmacological therapies due to their local irritations and side effects. Ectoine is a bacterial-derived extremolyte with an ability to protect proteins and biological membranes against damage caused by extreme conditions of salinity, drought, irradiation, pH, and temperature. Evidence from preclinical and clinical studies attests its effectiveness in the treatment of several inflammatory diseases, including allergic rhinitis. In this review, we analyzed 14 recent clinical trials investigating ectoine nasal spray in patients with allergic rhinitis and/or conjunctivitis, including sensitive patient groups like children or pregnant women. Some studies investigated monotherapy with ectoine; others investigated combination therapy of ectoine and an antihistamine or a corticosteroid. Analysis of the study results demonstrated that patients with mild-to-moderate symptoms of allergic rhinitis can be successfully treated with ectoine-containing nasal spray. When applied as monotherapy, ectoine exerted noninferior effects compared to first-line therapies such as antihistamines and cromoglicic acid. Using ectoine as an add-on therapy to antihistamines or intranasal glucocorticosteroids accelerated symptom relief by days and improved the level of symptom relief. Importantly, concomitant treatment with ectoine was proven beneficial in a group of difficult-to-treat patients suffering from moderate-to-severe rhinitis symptoms. Taken together, the natural substance ectoine represents a viable alternative for allergic rhinitis and conjunctivitis patients who wish to avoid local reactions and side effects associated with pharmacological therapies.

Genetic Deficiency and Pharmacological Stabilization of Mast Cells Ameliorate Pressure Overload-Induced Maladaptive Right Ventricular Remodeling in Mice.

Although the response of the right ventricle (RV) to the increased afterload is an important determinant of the patient outcome, very little is known about the underlying mechanisms. Mast cells have been implicated in the pathogenesis of left ventricular maladaptive remodeling and failure. However, the role of mast cells in RV remodeling remains unexplored. We subjected mast cell-deficient WBB6F1-KitW/W-v (KitW/KitW-v) mice and their mast cell-sufficient littermate controls (MC+/+) to pulmonary artery banding (PAB). PAB led to RV dilatation, extensive myocardial fibrosis, and RV dysfunction in MC+/+ mice. In PAB KitW/KitW-v mice, RV remodeling was characterized by minimal RV chamber dilatation and preserved RV function. We further administered to C57Bl/6J mice either placebo or cromolyn treatment starting from day 1 or 7 days after PAB surgery to test whether mast cells stabilizing drugs can prevent or reverse maladaptive RV remodeling. Both preventive and therapeutic cromolyn applications significantly attenuated RV dilatation and improved RV function. Our study establishes a previously undescribed role of mast cells in pressure overload-induced adverse RV remodeling. Mast cells may thus represent an interesting target for the development of a new therapeutic approach directed specifically at the heart.

Hydrophobic ion pair loaded self-emulsifying drug delivery system (SEDDS): A novel oral drug delivery approach of cromolyn sodium for management of bronchial asthma.

The aim of the present study is to develop a self-emulsifying drug delivery system (SEDDS) for the hydrophobic ion pair (HIP) complex of cromolyn sodium (CS), in order to enhance its intestinal absorption and biological activity. Two ion pairing agents (IPAs) were investigated: hexadecyl pyridininum chloride (HPC) and myristyl trimethyl ammonium bromide (MTAB). The optimum binding efficiency for complexation between investigated IPAs and CS was observed at a molar ratio of 1.5:1, where CS binding efficiency was found to be 76.10 ± 2.12 and 91.37 ± 1.73% for MTAB and HPC, respectively. The two prepared complexes exhibited a significant increase in partition coefficient indicating increased lipophilicity. The optimized CS-HIP complex was incorporated into SEDDS formulations. SEDDS formulations F2 (40% oleic acid, 40% BrijTM98, 20% propylene glycol) and F3 (25% oleic acid, 50% BrijTM98, 25% propylene glycol) exhibited nanometric droplet diameters with monodisperse distribution and nearly neutral zeta potential values. Ex vivo intestinal permeation study, using the non-everted gut sac technique, revealed a significantly higher cumulative amount of permeated drug, after 2 h, for F2 and F3 (53.836 and 77.617 µg/cm2, respectively) compared to 8.649 µg/cm2 for plain CS solution. The in vivo evaluation of plain CS solution compared to F2 and F3 was conducted in an ovalbumin sensitization-induced bronchial asthma rat model. Lung function parameters (tidal volume and peak expiratory flow), biochemical parameters (interleukin-5, immunoglobulin-E, myeloperoxidase and airway remodelling parameters) were assessed in addition to histopathological examination. The results indicated the superiority of F3 followed by F2 compared to plain CS solution for prophylaxis of bronchial asthma in rats.

Sodium chromo-glycate and palmitoylethanolamide: A possible strategy to treat mast cell-induced lung inflammation in COVID-19.

A novel human coronavirus SARS-CoV-2 (also referred to as CoV-19) that emerged in late 2019 causes Covid-19 disease a respiratory tract infection which provokes about 4 million deaths per year. Unfortunately, to date, there is no specific antiviral treatment for COVID-19. Mast cells (MCs) are immune cells implicated in the pathogenesis of viral infections, where they mediate inflammation. Microbes, including virus, activate MCs through TLR releasing chemical pro-inflammatory compounds and cytokines. Although, in biomedical literature there are only few reports on MCs activation by SARS-CoV-2 infection. The production of pro-inflammatory cytokines by MC viral activation leads to increase pulmonary inflammation and fibrosis. Sodium Chromo-Glycate (SCG) described as a MC stabilizer, prevents the release of inflammatory chemical compounds, improve mouse survival and respiratory pathological changes in lung viral infection and suppresses inflammation. Furthermore, palmitoylethanolamide (PEA) a nuclear factor agonist, an endogenous fatty acid amide, which exerts a variety of biological effects, related to chronic inflammation and pain, is involved also in MCs homeostasis with an inhibitory and protective effect on the respiratory tract during viral infections. Here, we hypothesize for the first time, that SCG and/or PEA suppress MC activation and pro-inflammatory mediators release, playing an anti-inflammatory therapeutic role in the inflamed lung of patients with COVID-19.

In vitro assessment of an idealized nose for nasal spray testing: Comparison with regional deposition in realistic nasal replicas.

An idealized nasal replica that mimics average regional deposition of nasal spray pump droplets in human nasal airways would potentially be useful in expediting the development of nasal spray products. The aim of this study was to validate an idealized nose, previously developed using in silico simulations, by comparing with regional deposition in realistic, sectioned nasal replicas obtained from in vitro deposition experiments. The realistic nasal airway replicas of five subjects obtained from computerized tomography were manufactured in plastic using rapid prototyping. The idealized nose was made using the same build procedure. A commercial nasal spray pump (NasalCrom, 5.2 mg cromolyn sodium per spray) was then actuated repeatably into each replica under a steady inspiratory flow of 7.5 L/min at two different orientations (45° and 60° from the horizontal). Sectioned replicas were disassembled, and the mass fraction of drug deposited on the surface of each anatomical region was determined. It was found that regional deposition of spray droplets in the idealized replica agreed well with average regional deposition in the realistic replicas. Regional deposition also agreed with previously published in vivo regional deposition using the same spray pump.

TCTP from Loxosceles Intermedia (Brown Spider) Venom Contributes to the Allergic and Inflammatory Response of Cutaneous Loxoscelism.

LiTCTP is a toxin from the Translationally Controlled Tumor Protein (TCTP) family identified in Loxosceles brown spider venoms. These proteins are known as histamine-releasing factors (HRF). TCTPs participate in allergic and anaphylactic reactions, which suggest their potential role as therapeutic targets. The histaminergic effect of TCTP is related to its pro-inflammatory functions. An initial characterization of LiTCTP in animal models showed that this toxin can increase the microvascular permeability of skin vessels and induce paw edema in a dose-dependent manner. We evaluated the role of LiTCTP in vitro and in vivo in the inflammatory and allergic aspects that undergo the biological responses observed in Loxoscelism, the clinical condition after an accident with Loxosceles spiders. Our results showed LiTCTP recombinant toxin (LiRecTCTP) as an essential synergistic factor for the dermonecrotic toxin actions (LiRecDT1, known as the main toxin in the pathophysiology of Loxoscelism), revealing its contribution to the exacerbated inflammatory response clinically observed in envenomated patients.

Activation of Mast Cells Promote Plasmodium berghei ANKA Infection in Murine Model.

Malaria, a mosquito-borne infectious disease, is a severe health problem worldwide. As reported, some anti-malarial drugs with anti-parasitic properties also block mast cells (MCs) activities. It is hypothesized that MCs activity may be correlated with the pathogenesis of malaria. Thus, the role of MCs on malarial pathogenesis and the involved physiological action and pathways need to be further investigated. This study aimed to investigate the effect of MCs activation on malaria disease severity using KunMing mice with Plasmodium berghei ANKA (PbANKA) infection treated with MCs degranulator (compound 48/80, C48/80) or MCs stabilizer (disodium cromoglycate, DSCG). PbANKA infection caused a dramatic increase in MCs density and level of MCs degranulation in cervical lymph node (CLN) and skin. Compared with infected control, C48/80 treatment had shortened survival time, increased parasitemia, exacerbated liver inflammation and CLN hyperplasia, accompanied with increase in vascular leakage and leukocyte number. The infected mice with C48/80 treatment also elevated the release of CCL2, CXCL1, and MMP-9 from MCs in CLN and skin, and TNF-α, IFN-γ, CCR2, and CXCR2 mRNA expression in CLN and liver. In contrast, the infected mice treated with DSCG showed longer survival time, lower parasitemia, improved liver inflammation and CLN hyperplasia, followed by a decline of vascular leakage and leukocyte number. Decreased MCs-derived CCL2, CXCL1, and MMP-9 from CLN and skin, mRNA expression in CLN and liver (TNF-α, IFN-γ, CCR2, and CXCR2) were also observed in infected mice with DSCG treatment. Our data indicated that MCs activation may facilitate the pathogenesis of PbANKA infection.

IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization.

The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.

Successful mast-cell-targeted treatment of chronic dyspareunia, vaginitis, and dysfunctional uterine bleeding.

Dyspareunia, vaginitis and dysfunctional uterine bleeding (DUB) are common problems which, despite their polygenicity, commonly appear idiopathic and treatment-refractory. Mast cell (MC) activation syndrome (MCAS) is a newly-recognised, prevalent, chronic multisystem polymorbidity of general themes of inflammation ± allergic-type phenomena ± aberrant growth/development in assorted tissues. MCs produce significant quantities of heparin, too. As such, MCAS may underlie some cases of chronic dyspareunia, vaginitis or DUB. We report five such patients; all who responded well to MC-targeted treatment. We review aspects of MC biology and pathobiology of potential relevance to otherwise idiopathic persistent inflammatory or coagulopathic genital tract problems. Diagnostic testing for MCAS may be warranted in some patients with chronic dyspareunia, vaginitis or DUB (especially patients whose histories well fit the general profile of MCAS), and prospective therapeutic trials of MC-directed topical and/or systemic therapies may be warranted in such populations. Impact statement What is already known on this subject? Chronic, idiopathic, treatment-refractory female genital tract inflammation or bleeding are common problems for which mast cell (MC) disease, previously generally thought to consist of just rare cases of mastocytosis, and is seldom considered in the differential diagnosis. What do the results of this study add? The substantial prevalence of the newly recognised 'mast cell activation syndrome' (MCAS), featuring chronic inappropriate MC activation with little-to-no MC neoplasia, and its clinical presentation with chronic multisystem inflammation ± allergic-type phenomena ± aberrant growth/development in assorted tissues, raises the possibility that MCAS might underlie the aforementioned genital tract problems, especially in patients whose larger clinical presentations fit the MCAS profile. We report five example patients (among many more we have similarly treated) who enjoyed excellent responses to safe, inexpensive MC-targeted treatments, often given just intravaginally. What are the implications of these findings for clinical practice and/or further research? Our report identifies a potentially significant new MC-focused direction, of relevance to millions of affected women worldwide, for clinical treatment as well as for basic and clinical research, which historically has yielded major advancements disappointingly disproportionate to the scope of the affected population.

Cromolyn-crosslinked chitosan nanoparticles for the treatment of allergic rhinitis.

The aim of this work was to prepare new mucoadhesive nasal decongestant nanoparticles obtained by direct crosslinking between the cationic polymer chitosan and the anionic drug cromolyn. Different chitosan/cromolyn molar ratios were used in order to obtain nanoparticles of suitable size, encapsulation efficiency/drug loading and mucoadhesion. Moreover, the ability of the nanoparticles to deliver cromolyn into and through the nasal mucosa was evaluated. The obtained positively charged nanoparticles, sized 180-400 nm, showed interesting properties in terms of yield, mucoadhesion, encapsulation efficiency and drug loading. Release and permeation/penetration data indicated the ability of the nanoparticles to retain a high amount of cromolyn inside the mucosa, which is rich in mast cells. These findings suggest developing decongestant nanoparticles for potential treatment of allergic rhinitis.

A modified USP induction port to characterize nasal spray plume geometry and predict turbinate deposition under flow.

There is currently no in vitro technique for assessing plume geometry of nasal sprays under airflow conditions. However, a majority of FDA approved nasal products recommend that patients inhale during actuation. Therefore, a reproducible in vitro test that measures plume angles under physiologically relevant inhalation flow rates would be useful. The purpose of this study was to adapt the recently described Plume Induction Port Evaluator (PIPE) apparatus for nasal sprays under flow and correlate these with nasal cast deposition patterns. Mass Median Plume Angles (MMPAs) of four nasal spray formulations with increasing viscosities were determined using the PIPE apparatus in the absence and presence of airflow. MMPAs were then correlated to drug deposition within 3D printed nasal casts using airflow. We evaluated different inhalation instructions obtained from the package insert of nasal products. MMPAs significantly reduced (narrower angles) when using flow for the three formulations with the lowest viscosities. An increase in the turbinate deposition was observed in the nasal casts when just one of the nostrils was closed during inhalation, except by the highest viscosity formulation. The turbinate deposition numerically correlated with changes in the plume angles observed using PIPE.

Disodium Cromolyn and Anti-podoplanin Antibodies Strongly Inhibit Growth of BHK 21/C13-derived Fibrosarcoma in a Chick Embryo Chorioallantoic Membrane Model.

AIM: To characterize baby hamster kidney fibroblast (BHK 21/C13) cells and test the effects of antibodies against podoplanin and disodium cromolyn on BHK 21/C13 cell line-derived tumors grown on chick embryo chorioallantoic membrane (CAM). MATERIAL AND METHODS: BHK 21/C13 cell-derived fibrosarcomas developed in hamsters were implanted on CAM and treated with anti-podoplanin antibodies and disodium cromolyn. BHK 21/C13 cell immunophenotype was assessed. RESULTS: Fibrosarcoma cells were positive for vimentin, CD117, smooth muscle actin, vascular endothelial growth factor epidermal growth factor receptor, homebox prospero gene 1 and negative for platelet-derived growth factor B, neuron-specific enolase, S100, CD34, Ewing sarcoma and podoplanin. CAM-grown fibrosarcomas were highly sensitive to disodium cromolyn and anti-podoplanin antibodies. CONCLUSION: Immunophenotyping BHK 21/C13 cells and their response to drugs represent the first step in revealing cell line utility and a reliable tool for experimental cancer research.

Disodium cromoglycate may act as a novel adjuvant for UV-attenuated Toxoplasma gondii vaccine in mouse model.

We have proven the beneficial effects during acute Toxoplasma gondii infection when mast cells were inhibited by disodium cromoglycate (DSCG). Here we investigated the adjuvant effect of DSCG on the protective efficacy of UV-attenuated T. gondii (UV-Tg) vaccine. Mice were infected with 102Tg alone or infected with 102Tg plus DSCG (Tg + DSCG), immunized with 105 UV-Tg and challenged with 102Tg (UV-Tg + Tg) or immunized with 105 UV-Tg plus DSCG and challenged with 102Tg (UV-Tg + DSCG + Tg). Compared to Tg group, Tg + DSCG, UV-Tg + Tg, and UV-Tg + DSCG + Tg showed significantly prolonged survival times, decreased parasite burdens, reduced liver histopathologies, and increased levels of Th1 and Th2 cytokines and IL-17 in the livers and spleens by using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Compared to UV-Tg + Tg, UV-Tg + DSCG + Tg had significantly longer survival time, lower tissue parasite burden and histopathological score, and higher levels of Th1 and Th2 cytokines and IL-17 in the livers or spleens. Our data suggest that DSCG may play an adjuvant role in the immunization induced by UV-attenuated T. gondii in mice, by promoting cellular immune response against T. gondii challenge.

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial.

BACKGROUND: Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. METHODS: This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. FINDINGS: Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48-0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78-2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. INTERPRETATION: This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation. FUNDING: Patara Pharma.

Formulation and Characterization of Polysaccharide Microparticles for Pulmonary Delivery of Sodium Cromoglycate.

Sodium cromoglycate (SC) is an antiasthmatic and antiallergenic drug commonly used for chronic inhalation therapy; however, many daily intakes are required due to the fast drug clearance from airways. For these reasons, SC polymeric particles for inhalatory administration with adequate aerosolization and mucoadhesive properties were designed to prolong the drug residence time in the site of action. Sodium carboxymethylcellulose (CMCNa), sodium hyaluronate, and sodium alginate were selected to co-process SC by spray drying. The influence of these polysaccharides on the spray drying process and powder quality was evaluated (among others, morphology, size, moisture content, hygroscopicity, flowability, densities, liquid sorption, and stability). In vitro aerosolization, drug release, and mucoadhesion performance were also studied. Particularly, a novel method to comparatively evaluate the interaction between formulations and mucin solution (mucoadhesion test) was proposed as a rapid methodology to measure adhesion properties of inhalable particles, being the results as indicative of clearance probability. Among all the studied formulations, the powder based on SC and CMCNa exhibited the best mucoadhesion and aerosolization performance, the highest process yield and adequate moisture content, hygroscopicity, and stability. SC-CMCNa formulation arose as a promising inhalatory system to reduce the daily intakes and to increase the patient compliance.

Effect of Intervention in Mast Cell Function Before Reperfusion on Renal Ischemia-Reperfusion Injury in Rats.

BACKGROUND/AIMS: Mast cells are sparsely distributed in the kidneys under normal conditions; however, the number of mast cells increases dramatically during renal ischemia/reperfusion injury (RI/RI). When mast cells are stimulated, numerous mediators are released, and under pathological conditions, they produce a wide range of biological effects. The aim of this study was to investigate the effect of intervention in mast cell function before reperfusion on RI/RI. METHODS: Sprague-Dawley (SD) rats (n=50) were randomized into five groups: sham group, ischemia/reperfusion (I/R) group, cromolyn sodium treatment group (CS+I/R group), ketotifen treatment group (K+I/Rgroup), and compound 48/80 treatment group (C+I/R group). I/R injury was induced by bilateral renal artery and vein occlusion for 45 min followed by 24 h of reperfusion. The agents were intravenously administered 5 min before reperfusion through the tail vein. The serum levels of blood urea nitrogen(BUN), serum creatinine (Scr) and histamine and the kidney levels of malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) were assessed. The expression of intracellular adhesion molecule-1 (ICAM-1) in renal tissue was also measured. RESULTS: I/R injury resulted in severe renal injury, as demonstrated by a large increase in injury scores; serum levels of BUN, Scr and histamine; and kidney levels of MDA, TNF-α, and IL-6; this was accompanied by reduced SOD activity and upregulated ICAM-1 expression. Treatment with cromolyn sodium or ketotifen markedly alleviated I/R-mediated kidney injury, whereas compound 48/80 further aggravated kidney injury. CONCLUSION: Intervention in mast cell activity prior to reperfusionhas a strong effect on RI/RI.

Ovalbumin-induced allergic inflammation lead to structural alterations in mouse model and protective effects of intranasal curcumin: A comparative study.

BACKGROUND: Antigen exposure and persistent inflammation leads to structural changes in the asthmatic airways which are collectively termed as "airway remodelling". Presently available asthma medications ameliorate inflammations but are unable to prevent or reverse the airway remodelling process as most of the treatment strategies are only focused on inflammation instead of remodelling. METHODS: Curcumin, a phytochemical present in the rhizome of Curcuma longa is well known for its anti-inflammatory activity; however, the main drawback is its poor bioavailability which limits its therapeutic approval. So, the effect of nasal curcumin on acute and chronic asthma has been studied where short exposure to ovalbumin (4 days) represents acute phase whereas repeated exposures for longer (twice per week till 5 weeks) represents chronic asthma. Disodium cromoglycate (DSCG, 50mg/kg, i.p.) and dexamethasone (1mg/kg, i.p.) were used as standard drugs in acute and chronic model of asthma respectively. RESULTS: OVA-induced airway inflammation initiated in acute stage led to remodelling due to persistent inflammation, epithelial and sub epithelial thickening (smooth muscle thickening), extracellular matrix (ECM) deposition, goblet cell hyperplasia and mucus plug formation. Intranasal curcumin is effective in inhibiting airway inflammation and remodelling both by maintaining the structural integrity of lungs in terms of inflammation, airway wall thickening and mucus production. CONCLUSION: Our findings suggest that curcumin administered through nasal route might prove therapeutically efficient in inhibiting allergic airway inflammations and maintaining structural integrity in the mouse model of allergic asthma. This may lead to the development of curcumin aerosol in near future.

Mast Cell Inhibition Attenuates Cardiac Remodeling and Diastolic Dysfunction in Middle-aged, Ovariectomized Fischer 344 × Brown Norway Rats.

The incidence of left ventricular diastolic dysfunction (LVDD) increases in women after menopause, yet the mechanisms are unclear. Because mast cells participate in the pathological processes of various cardiac diseases, we hypothesized that mast cell inhibition would protect against estrogen loss-induced LVDD. The mast cell stabilizer, cromolyn sodium (30 mg·kg·d), or vehicle was administered subcutaneously by osmotic minipump to ovariectomized (OVX) female Fischer 344 × Brown Norway (F344BN) rats starting at 4 weeks after surgery. Eight weeks after OVX, systolic blood pressure increased by 20% in OVX versus sham rats, and this effect was attenuated after 4 weeks of cromolyn treatment. Also, cromolyn mitigated the adverse reductions in myocardial relaxation (e') and increases in left ventricle (LV) filling pressures (E/e'), LV mass, wall thicknesses, and interstitial fibrosis from OVX. Although cardiac mast cell number was increased after OVX, cardiac chymase activity was not overtly altered by estrogen status and tended to decrease by cromolyn. Contrariwise, Ang II content was greater in hearts of OVX versus sham rats, and cromolyn attenuated this effect. Taken together, mast cell inhibition with cromolyn attenuates LV remodeling and LVDD in OVX-Fischer 344 × Brown Norway rats possibly through actions on the heart level and/or through vasodilatory effects at the vascular level.

Highly water-soluble mast cell stabiliser-encapsulated solid lipid nanoparticles with enhanced oral bioavailability.

Cromolyn sodium (CS), a mast cell stabiliser, is widely employed for the prevention and treatment of allergic conditions. However, high hydrophilicity and poor oral permeability hinder its oral clinical translation. Here, solid lipid nanoparticles (SLNs) have been developed for the purpose of oral bioavailability enhancement. The CS-SLNs were engineered by double emulsification method (W1/O/W2) and optimised by using Box-Behnken experimental design. The surface and solid-state characterisations revealed the presence of CS in an amorphous form without any interactions inside the spherical-shaped SLNs. The in-vitro release study showed an extended release up to 24 hr by diffusion controlled process. Ex-vivo and in-vivo intestinal permeation study showed ∼2.96-fold increase in permeability of CS by presentation as SLNs (p < 0.05). Further, in-vivo pharmacokinetic study exhibited ∼2.86-fold enhancements in oral bioavailability of CS by encapsulating inside SLNs, which clearly indicate that SLNs can serve as the potential therapeutic carrier system for oral delivery of CS.

The therapeutic effects of sodium cromoglycate against influenza A virus H5N1 in mice.

OBJECTIVES: To identify the protective role of sodium cromoglycate in mice during influenza virus infection. DESIGN: H5N1 virus-infected mice were treated with the mast cell stabilizer sodium cromoglycate (SCG) to investigate its therapeutic effect. SAMPLE: The nose, trachea and lungs from mice were collected. MAIN OUTCOME MEASURES: Virus replication and host responses were determined by plaque assay, quantitative PCR, immunohistochemistry, and histology. RESULTS: SCG-treated mice survived better than did PBS-treated mice after H5N1 virus infection. Mild pathological changes with fewer inflammatory cell infiltration and fewer virus antigens were observed in the nose, trachea, and lungs of SCG-treated mice on days 3 and 5 post-infection. However, no significant changes in viral load in the lungs were detected between SCG- and PBS-treated mice. Furthermore, significantly decreased expression of interleukin-6, tumor necrosis factor-a, Toll-like receptor 3, and TIR-domain-containing adapter-inducing interferon-b was detected in the lungs of SCG-treated mice, and no higher expression of interferon-c was detected. CONCLUSION: These results suggest that SCG has therapeutic roles in H5N1 virus-infected mice by alleviating the inflammatory response rather than inhibition of viral replication in the lungs.