Aluminum Hydroxide Suspension Research Articles

Paeoniflorin inhibits PRAS40 interaction with Raptor to activate mTORC1 to reverse excessive autophagy in airway epithelial cells for asthma

BackgroundBronchial asthma is a chronic condition characterized by airway inflammation and remodeling, which pose complex pathophysiological challenges. Autophagy has been identified as a practical strategy to regulate inflammation and remodeling processes in chronic inflammatory diseases with pathological characteristics, such as asthma. PF (Paeoniflorin) is a potential new autophagy regulatory compound. Previous studies have reported that PF can inhibit airway inflammation to alleviate allergic asthma, but whether this is mediated through the regulation of autophagy and the molecular mechanism of action remains unclear. PurposeThe aim of this study was to evaluate the inhibitory effect of natural small molecule PF on asthma by regulating epithelial autophagy. MethodsThe rat asthma model was established through intraperitoneal injection of OVA and aluminum hydroxide suspension, followed by atomized inhalation of OVA for a period of two weeks. Following treatment with PF, histopathology was observed using Masson and H&E staining, while airway Max Rrs was evaluated using a pulmonary function apparatus. Levels of inflammatory cells in BALF were detected using a blood cell analyzer, and levels of inflammatory factors in BALF were detected through Elisa. Expressions of p-PRAS40 and p-Raptor were observed through immunohistochemistry, and levels of Beclin1 and LC3B were observed through immunofluorescence. The structure and quantity of autophagosomes and autophagolysosomal were observed through TEM. An autophagy model of 16HBE cells was established after treatment with 10ng/mL IL13 for 30 minutes. PRAS40 (AKT1S1) overexpression and mutation of PF and Raptor binding site (K207M& L302I& Q417H) were introduced in 16HBE cells. Autophagy in cells was measured by mFRP-GFP-LC3 ADV fluorescent tracer. The binding sites of PF and Raptor were analyzed using the Autodock Tool. The p-mTOR, p-Raptor, p-PRAS40, LC3II/LC3I were detected through Western blot, and interaction between PRAS40-Raptor and Raptor-mTOR was detected through Co-IP. ResultsThe results showed that PF effectively reduced airway inflammation, improved airway pathological changes and remodeling, and maintained lung function. Additionally, PF was found to reverse excessive autophagy in airway epithelial cells. Interestingly, PF activated the mTORC1 subunit PRAS40 and Raptor in airway epithelial cells by regulating their phosphorylation. PRAS40 is an endogenous mTOR inhibitor that promotes autophagy. PF competitively binds Raptor to PRAS40, promoting Raptor-mTOR interactions to activate mTORC1, an outcome that can be reversed by PRAS40 overexpression and site-specific amino acid codon mutations in Raptor. ConclusionThese findings suggest that PF intervention and inhibition of PRAS40-Raptor interaction are effective treatments for bronchial asthma. By activating mTORC1, PF effectively reverses excessive autophagy in airway epithelial cells, leading to improved airway function and reduced inflammation.

Effect of acupoint catgut embedding on p38 MAPK pathway in the lung tissue of asthmatic rats.

To observe the effect of catgut embedding at "Feishu"(BL13), "Dingchuan" (EX-B1) and "Danzhong" (CV17) on expression of phosphorylated p38 mitogen activated protein kinase (p-p38 MAPK), interleukin-4 (IL-4), interferon-γ (IFN-γ) and changes of airway epithelial cells (AEC) in the lung tissue of bronchial asthma (BA) rats, so as to explore its mechanisms underlying improvement of BA. Forty male Wistar rats were randomly and equally divided into blank control, model, dexamethasone (DEX) and catgut embedding groups. The BA model was established by intraperitoneal injection of suspension of ovalbumin and aluminum hydroxide. Rats of the DEX group received intraperitoneal injection of DEX (1.5 mg/kg), once daily for 2 weeks, and those of the catgut embedding group received catgut embedding at BL13, EX-B1 and CV17 only one time. The rats' sneezing times per miniute in each group were recorded. H.E. staining was used to observe the histopathological changes of the lung tissue under light microscope. A transmission electron microscope (TEM) was used to observe the ultrastructural changes of AEC in the lung tissue, including the thickness of bronchial wall and bronchial smooth muscle by using an image analysis software. The protein expressions of p-p38 MAPK, IL-4 and INF-γ in the lung tissue were determined using Western blot. Morphological observation revealed that in the model group, light microscope showed deformed and swollen bronchial tube wall with increased folds and thickened bronchial smooth muscle；and TEM showed a large number of autophagy vesicles containing swollen and deformed organelles in the AEC, and apparent reduction of intracellular mitochondria, these situations were obviously milder in both DEX and catgut embedding groups. Compared with the blank control group, the sneezing times, thickness of bronchial wall and bronchial smooth muscle in the model group were significantly increased (P<0.01), and the expressions of p-p38 MAPK and IL-4 in lung tissue were significantly increased (P<0.01), while the expression of IFN-γ was significantly decreased (P<0.01) in the model group. In comparison with the model group, the sneezing times, thickness of bronchial wall and bronchial smooth muscle, protein expressions of p-p38 MAPK and IL-4 were significantly decreased (P<0.01), while the expression of IFN-γ was obviously increased (P<0.01) in both the DEX and catgut embedding groups. Acupoint catgut embedding can reduce the expression of IL-4 and increase the expression of IFN-γ by inhibiting p38 MAPK signal pathway of lung tissues in BA rats, which may contribute to its effect in alleviating the degree of airway epithelial cells damage.

Safety and immunogenicity of a trivalent virus-like particle vaccine against western, eastern, and Venezuelan equine encephalitis viruses: a phase 1, open-label, dose-escalation, randomised clinical trial

Western (WEEV), eastern (EEEV), and Venezuelan (VEEV) equine encephalitis viruses are mosquito-borne pathogens classified as potential biological warfare agents for which there are currently no approved human vaccines or therapies. We aimed to evaluate the safety, tolerability, and immunogenicity of an investigational trivalent virus-like particle (VLP) vaccine, western, eastern, and Venezuelan equine encephalitis (WEVEE) VLP, composed of WEEV, EEEV, and VEEV VLPs. The WEVEE VLP vaccine was evaluated in a phase 1, randomised, open-label, dose-escalation trial at the Hope Clinic of the Emory Vaccine Center at Emory University, Atlanta, GA, USA. Eligible participants were healthy adults aged 18-50 years with no previous vaccination history with an investigational alphavirus vaccine. Participants were assigned to a dose group of 6 μg, 30 μg, or 60 μg vaccine product and were randomly assigned (1:1) to receive the WEVEE VLP vaccine with or without aluminium hydroxide suspension (alum) adjuvant by intramuscular injection at study day 0 and at week 8. The primary outcomes were the safety and tolerability of the vaccine (assessed in all participants who received at least one administration of study product) and the secondary outcome was immune response measured as neutralising titres by plaque reduction neutralisation test (PRNT) 4 weeks after the second vaccination. This trial is registered at ClinicalTrials.gov, NCT03879603. Between April 2, 2019, and June 13, 2019, 30 trial participants were enrolled (mean age 32 years, range 21-48; 16 [53%] female participants and 14 [47%] male participants). Six groups of five participants each received 6 μg, 30 μg, or 60 μg vaccine doses with or without adjuvant, and all 30 participants completed study follow-up. Vaccinations were safe and well tolerated. The most frequently reported symptoms were mild injection-site pain and tenderness (22 [73%] of 30) and malaise (15 [50%] of 30). Dose-dependent differences in the frequency of pain and tenderness were found between the 6 μg, 30 μg, and 60 μg groups (p=0·0217). No significant differences were observed between dosing groups for any other reactogenicity symptom. Two adverse events (mild elevated blood pressure and moderate asymptomatic neutropenia) were assessed as possibly related to the study product in one trial participant (60 μg dose with alum); both resolved without clinical sequelae. 4 weeks after second vaccine administration, neutralising antibodies were induced in all study groups with the highest response seen against all three vaccine antigens in the 30 μg plus alum group (PRNT80 geometric mean titre for EEEV 60·8, 95% CI 29·9-124·0; for VEEV 111·5, 49·8-249·8; and for WEEV 187·9, 90·0-392·2). Finally, 4 weeks after second vaccine administration, for all doses, the majority of trial participants developed an immune response to all three vaccine components (24 [83%] of 29 for EEEV; 26 [90%] of 29 for VEEV; 27 [93%] of 29 for WEEV; and 22 [76%] of 29 for EEEV, VEEV, and WEEV combined). The favourable safety profile and neutralising antibody responses, along with pressing public health need, support further evaluation of the WEVEE VLP vaccine in advanced-phase clinical trials. The Vaccine Research Center of the National Institute of Allergy and Infectious Diseases, National Institutes of Health funded the clinical trial. The US Department of Defense contributed funding for manufacturing of the study product.

Neuroprotective effect of dapsone in patients with aneurysmal subarachnoid hemorrhage: a prospective, randomized, double-blind, placebo-controlled clinical trial.

In this study, the authors sought to define the differences in the incidence of delayed cerebral ischemia (DCI) between patients treated with dapsone and those treated with placebo. Secondary objectives were to define the clinical outcome at discharge and 3 months and the incidence of brain infarction. A prospective, randomized, double-blind, placebo-controlled study was performed and included patients with aneurysmal subarachnoid hemorrhage (SAH) within 5 days from ictus who were candidates for aneurysm occlusion, and who had a Fisher grade of 3 or 4. Patients with sulfa or sulfone drug allergies, hemoglobin < 11 g/dl, known G6PD deficiency, and those refusing informed consent were excluded. A minimal relevant effect decrease of 35% in the incidence of DCI was established. Patients were randomly assigned to receive a regimen of dapsone 2.5 ml (100 mg) daily or a placebo (aluminum hydroxide suspension, 2.5 ml daily). Both groups received validated treatment for aneurysmal SAH. The appearance of DCI on CT was assessed in every patient at discharge and 3 months later. We used the chi-square test to compare the DCI incidence between both groups, and the Student t-test or nonparametric tests to compare quantitative variables. Overall, 48 patients (70.8% women and 29.2% men) were included. The mean age was 50 years (SD 14.28 years, range 18-72 years). Prerandomization and postrandomization characteristics were balanced, except for the necessity of intra-arterial nimodipine administration in patients treated with placebo (15.4% vs 45.5%, p = 0.029. The incidence of DCI, the primary endpoint, for the whole cohort was 43.8% and was significantly lower in the dapsone group (26.9% vs 63.6%, p = 0.011). In addition, the irreversible DCI incidence was lower in the dapsone group (11.5% vs 54.5%, p = 0.12). A favorable modified Rankin Scale score was more frequent in the dapsone group at discharge and at 3 months (76.9% vs 36.4%, p = 0.005 and 80% vs 38.9%, p = 0.019, respectively). Also, the brain infarction incidence was lower in the dapsone group (19.2% vs 63.6%, p = 0.001). There was no difference between groups regarding adverse events. Dapsone seems to play a role as a prophylactic agent in patients at high risk of developing DCI after aneurysmal SAH. A multicenter investigation is necessary to increase the study population and confirm the consistency of the results observed in this study.

Clerodendrum serratum extract attenuates production of inflammatory mediators inovalbumin-induced asthma in rats

In the present study, ethanolic extract of Clerodendrum serratum roots was investigated for its potential to reverse some features of bronchial asthma in ovalbumin-induced murine model of asthma. Clerodendrum serratum commonly called bharangi, (family Solanaceae) is a well-known anti-allergic drug in Asian folk system of medicines. In the present work, pharmacological studies are done to provide scientific evidence for therapeutic potential of plant in allergic asthma. Asthma was induced in experimental rats with allergen suspension of ovalbumin and aluminum hydroxide followed by treatment with dexamethasone (2.5 mg/kg, po) or C. serratum root extract (0.53 and 5.3 mg/kg, b. w., po). Biomarkers of inflammatory response including cell counts, immunoglobulin E, cytokines such as interleukin (IL) -4, -5, -1β, tumor necrosis factor- α (TNF-α), leukotriene (LTD-4), and nitrite concentration in blood as well as bronchial (BAL) fluid were tested. Lung functions in asthmatic and treated animals were evaluated as breathing rate and tidal volume. Treatment with C. serratum extract markedly (p < 0.001, p < 0.01, and p < 0.05) diminished infiltration of inflammatory cells, IgE, cytokines, and nitrites in blood serum and bronchial fluid. Improvement in lung functions (p < 0.05) of asthmatic animals after CSE treatment also supports our findings. Results of the study suggest therapeutic potential of C. serratum in allergic asthma that can be related to ability of plant to attenuate response of inflammatory cells and thereby, production of inflammatory and proinflammatory cytokines in airways.

Clerodendrum serratum extract attenuates production of inflammatory mediators in ovalbumin-induced asthma in rats.

In the present study, ethanolic extract of Clerodendrum serratum roots was investigated for its potential to reverse some features of bronchial asthma in ovalbumin-induced murine model of asthma. Clerodendrum serratum commonly called bharangi, (family Solanaceae) is a well-known anti-allergic drug in Asian folk system of medicines. In the present work, pharmacological studies are done to provide scientific evidence for therapeutic potential of plant in allergic asthma. Asthma was induced in experimental rats with allergen suspension of ovalbumin and aluminum hydroxide followed by treatment with dexamethasone (2.5 mg/kg, po) or C. serratum root extract (0.53 and 5.3 mg/kg, b. w., po). Biomarkers of inflammatory response including cell counts, immunoglobulin E, cytokines such as interleukin (IL) -4, -5, -1β, tumor necrosis factor-α (TNF-α), leukotriene (LTD-4), and nitrite concentration in blood as well as bronchial (BAL) fluid were tested. Lung functions in asthmatic and treated animals were evaluated as breathing rate and tidal volume. Treatment with C. serratum extract markedly (p < 0.001, p < 0.01, and p < 0.05) diminished infiltration of inflammatory cells, IgE, cytokines, and nitrites in blood serum and bronchial fluid. Improvement in lung functions (p < 0.05) of asthmatic animals after CSE treatment also supports our findings. Results of the study suggest therapeutic potential of C. serratum in allergic asthma that can be related to ability of plant to attenuate response of inflammatory cells and thereby, production of inflammatory and proinflammatory cytokines in airways.

Immunogenicity of Antigen Adjuvanted with AS04 and Its Deposition in the Upper Respiratory Tract after Intranasal Administration.

Adjuvant system 04 (AS04) is in injectable human vaccines. AS04 contains two known adjuvants, 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and insoluble aluminum salts. Data from previous studies showed that both MPL and insoluble aluminum salts have nasal mucosal vaccine adjuvant activity. The present study was designed to test the feasibility of using AS04 as an adjuvant to help nasally administered antigens to induce specific mucosal and systemic immunity as well as to evaluate the deposition of antigens in the upper respiratory tract when adjuvanted with AS04. Alhydrogel, an aluminum (oxy)hydroxide suspension, was mixed with MPL to form AS04, which was then mixed with ovalbumin (OVA) or 3× M2e-HA2, a synthetic influenza virus hemagglutinin fusion protein, as an antigen to prepare OVA/AS04 and 3× M2e-HA2/AS04 vaccines, respectively. In mice, AS04 enabled antigens, when given intranasally, to induce specific IgA response in nasal and lung mucosal secretions as well as specific IgG response in the serum samples of the immunized mice, whereas subcutaneous injection of the same vaccine induced specific antibody responses only in the serum samples but not in the mucosal secretions. Splenocytes isolated from mice intranasally immunized with the OVA/AS04 also proliferated and released cytokines (i.e., IL-4 and IFN-γ) after in vitro stimulation with the antigen. In the immunogenicity test, intranasal OVA/AS04 was not more effective than intranasal OVA/MPL at the dosing regimens tested. However, when compared to OVA/MPL, OVA/AS04 showed a different atomized droplet size distribution and more importantly a more favorable OVA deposition profile when atomized into a nasal cast that was 3-D printed based on the computer tomography scan of the nose of a child. It is concluded that AS04 has mucosal adjuvant activity when given intranasally. In addition, there is a reason to be optimistic about using AS04 as an adjuvant to target an antigen of interest to the right region of the nasal cavity in humans for immune response induction.

Effect of artesunate on airway responsiveness and airway inflammation in asthmatic mice

Objective: To observe the effects of artesunate on airway responsiveness and airway inflammation in asthmatic mice. Methods: Thirty female BALB/c mice aged 6-8 weeks were randomly divided into control group, asthma group and artesunate group. In the asthma group and the artesunate group, the mice were sensitized by intraperitoneal injection of 20 μg of ovalbumin (OVA) and 0.2 ml of aluminum hydroxide suspension (2 mg) on day 0 and 14, respectively, and 1% OVA 10 ml dissolved in sterile phosphate (PBS) buffer was aerosolized for 30 min from the 21st to 28th day. The control group was sensitized with 0.2 ml of 2 mg suspension of aluminum hydroxide on day 0 and 14, and aerosolized by 10 ml of sterile PBS from the 21st to 28th day. Before the challenge, the artesunate group was intraperitoneally injected with 0.2 ml of artesunate. Artesunate was replaced with the same amount of normal saline in the control group and the asthma group. The mice were treated after 24 hours of last stimulation. The airway responsiveness of mice was measured by airway intubation and the changes of airway resistance and compliance were observed. Bronchoalveolar lavage fluid (BALF) was classified by cytology, and pathological changes of left lung tissue were observed and scored. Results: The airway resistance of the three groups increased and the lung compliance decreased with the increase of methacholine (Ach) concentration. The airway resistance and lung compliance of the three groups were different under the same concentration (P<0.05). The airway resistance of the artesunate group at Ach 6.25, 12.5, 25, 50, 100 mg/ml was lower than that of the asthma group at the same concentration [(1.01±0.48) vs (1.30±0.22), (1.06±0.44) vs (1.70±0.31), (1.30±0.64) vs (2.66±0.79), (1.82±0.55) vs (3.38±1.35), (2.49±0.85) vs (4.07±1.34) cmH(2)O·s(-1)·ml(-1)(1 cmH(2)O=0.098 kPa); t=3.862, 7.376, 9.113, 7.051, 6.685, all P<0.05]; the degree of lung compliance decrease at the concentration of Ach 3.125, 6.25, 12.5, 25, 50, 100 mg/ml was lower than that of the asthma group at the same concentration [(3.89±0.55)×10(-2) vs (3.07±0.63)×10(-2), (3.61±0.52)×10(-2) vs (3.04±0.58)×10(-2), (3.48±0.38)×10(-2) vs (2.78±0.57)×10(-2), (3.09±0.52)×10(-2) vs (1.73±0.62)×10(-2), (2.32±0.60)×10(-2) vs (1.29±0.54)×10(-2), (1.87±0.59)×10(-2) vs (1.15±0.44)×10(-2) ml/cmH(2)O; t=-6.295, -4.921, -6.533, -11.135, -8.48, -6.319, all P<0.05]. The proportion of eosinophils in artesunate group in BALF was significantly lower than that in asthma group [(16.63±8.58)% vs (40.44±12.94)%; t=4.336, P<0.05]. In the asthma group, the inflammatory cells infiltration of the bronchi and the perivascular area, the bronchial epithelial edema and degeneration can be observed, and the artesunate could reduce the infiltration of inflammatory cells around the bronchus and blood vessels, and the mucus secretion was also reduced in the artesunate group. Conclusion: Artesunate can improve airway hyperresponsiveness and airway inflammation in asthmatic mice and has a certain therapeutic effect on asthma.

Hydroconversion of radiation-activated sawdust in the presence of ultradispersed catalysts (Short Communication)

The joint hydroconversion of sawdust preliminarily irradiated on an isotopic γ-radiation source with the tar of carbonic crude oil was carried out in the presence of the precursors of ultradispersed catalysts: the aqueous solutions of ammonium paramolybdate and zirconium chloride and a suspension of aluminum hydroxide. Ammonium sulfide was used as a sulfidizing additive. It was found that the preliminary treatment of sawdust with γ-radiation at a dose of 800 Mrad significantly increased the yield of distillate products.

Stabilization of a recombinant ricin toxin A subunit vaccine through lyophilization

Lyophilization was used to prepare dry, glassy solid vaccine formulations of recombinant ricin toxin A-chain containing suspensions of colloidal aluminum hydroxide adjuvant. Four lyophilized formulations were prepared by using combinations of rapid or slow cooling during lyophilization and one of two buffers, histidine or ammonium acetate. Trehalose was used as the stabilizing excipient. Aggregation of the colloidal aluminum hydroxide suspension was reduced in formulations processed with a rapid cooling rate. Aluminum hydroxide particle size distributions, glass transition temperatures, water contents, and immunogenicities of lyophilized vaccines were independent of incubation time at 40°C for up to 15weeks. Mice immunized with reconstituted ricin toxin subunit A (RTA) vaccines produced RTA-specific antibodies and toxin-neutralizing antibodies (TNAs) regardless of the length of high temperature vaccine storage or the degree of aluminum adjuvant aggregation that occurred during lyophilization. In murine studies, lyophilized formulations of vaccines conferred protection against exposure to lethal doses of ricin, even after the lyophilized formulations had been stored at 40°C for 4weeks. A corresponding liquid formulation of vaccine stored at 40°C elicited RTA-specific antibody titers but failed to confer immunity during a ricin challenge.

Flow cytometry: An alternative method for direct quantification of antigens adsorbed to aluminum hydroxide adjuvant

Flow cytometry (FC) has been widely used in biological research; however, its use for vaccine characterization has been very limited. Here we describe the development of an FC method for the direct quantification of two Neisseria meningitidis vaccine antigens, in mono- and multivalent formulations, while still adsorbed on aluminum hydroxide (AH) suspension. The antibody-based method is specific and sensitive. Because FC allows microscopic particle examination, the entire aluminum suspension carrying adsorbed antigen(s) can be analyzed directly. In addition to determining antigen concentration and identity, the assay is able to determine the distribution of the antigens on AH. High correlation coefficients ( r 2) were routinely achieved for a broad range of antigen doses from 0 to 150 μg/dose. Traditional assays for quantitative and qualitative antigen characterization on AH particles involve either complete aluminum dissolution or antigen desorption from the adjuvant. Because our direct method uses the whole AH suspension, the cumbersome steps used by traditional methods are not required. Those steps are often inefficient in desorbing the antigens and in some cases can lead to protein denaturation. We believe that this novel FC-based assay could circumvent some of the complex and tedious antigen–adjuvant desorption methods.

Facile synthesis of Zn-Al layered double hydroxide from aqueous suspension of zinc oxide and aluminum hydroxide

Zn-Al layered double hydroxide containing benzenesulfonate was successfully synthesized by the hydrothermal reactions of aqueous suspension of zinc oxide and aluminum hydroxide in the presence of benzene sulfonic acid. The products were characterized by the sharp X-ray diffraction profile and platy particle morphology. The present very simple (hydrothermal reaction of the aqueous mixture) synthesis is applicable to a series of layered double hydroxides with different compositions and structures.

Interventions for treating oral mucositis for patients with cancer receiving treatment

AbstractBackground: Treatment of cancer is increasingly effective but associated with short and long‐term side effects. Oral side effects, including oral mucositis (mouth ulceration), remain a major source of illness despite the use of a variety of agents to treat them.Objectives: To assess the effectiveness of interventions for treating oral mucositis or its associated pain in patients with cancer receiving chemotherapy or radiotherapy or both.Search strategy: Computerized searches of Cochrane Oral Health Group’s Trials Register; Cochrane Pain, Palliative and Supportive Care Group’s Trials Register; CENTRAL; MEDLINE and EMBASE were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. Date of the most recent searches June 2006: CENTRAL (The Cochrane Library 2006, Issue 2).Selection criteria: All randomized controlled trials comparing agents prescribed to treat oral mucositis in people receiving chemotherapy or radiotherapy or both. Outcomes were oral mucositis, time to heal mucositis, oral pain, duration of pain control, dysphagia, systemic infection, amount of analgesia, length of hospitalization, cost and quality of life.Data collection and analysis: Data were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomization, blindness and withdrawals. Quality assessment was carried out on these three criteria. The Cochrane Oral Health Group statistical guidelines were followed and risk ratio (RR) values calculated using fixed effect models.Main results: Twenty‐six trials involving 1353 patients satisfied the inclusion criteria. Four agents, each in single trials, were found to be effective for improving (allopurinol RR 3.33, 95% confidence interval (CI) 1.06 to 10.49; granulocyte macrophage‐colony stimulating factor RR 4.23, 95% CI 1.35 to 13.24; immunoglobulin RR 1.81, 95% CI 1.24 to 2.65; human placentral extract RR 4.50, 95% CI 2.29 to 8.86) or eradicating mucositis (allopurinol RR 19.00, 95% CI 1.17 to 307.63). Three of these trials were rated as at moderate risk of bias and one as at high risk of bias. The following agents were not found to be effective: benzydamine HCl, sucralfate, tetrachlorodecaoxide, chlorhexidine and ‘magic’ (lidocaine solution, diphenhydramine hydrochloride and aluminum hydroxide suspension). Six trials compared the time to heal and mucositis was found to heal more quickly with two interventions: granulocyte macrophage‐colony stimulating factor when compared to povidone iodine, with mean difference −3.5 days (95% CI −4.1 to −2.9) and allopurinol compared to placebo, with mean difference −4.5 days (95% CI −5.8 to −3.2).Three trials compared patient controlled analgesia (PCA) to the continuous infusion method for controlling pain. There was no evidence of a difference, however, less opiate was used per hour for PCA, and the duration of pain was shorter. One trial demonstrated that pharmacokinetically based analgesia (PKPCA) reduced pain compared with PCA: however, more opiate was used with PKPCA.Authors’ conclusions: There is weak and unreliable evidence that allopurinol mouthwash, granulocyte macrophage‐colony stimulating factor, immunoglobulin or human placental extract improve or eradicate mucositis. There is no evidence that patient controlled analgesia (PCA) is better than continuous infusion method for controlling pain, however, less opiate was used per hour, and duration of pain was shorter, for PCA. Further, well designed, placebo‐controlled trials assessing the effectiveness of allopurinol mouthwash, granulocyte macrophage‐colony stimulating factor, immunoglobulin, human placental extract, other interventions investigated in this review and new interventions for treating mucositis are needed.

Challenge with ovalbumin antigen increases uterine and cervical contractile activity in sensitized guinea pigs

The aims of this study were to investigate the effects of ovalbumin challenge on uterine and cervical contractility, intrauterine pressure, and uterine electromyography activity in sensitized guinea pigs. Guinea pigs were sensitized by injection of ovalbumin-aluminum hydroxide suspension. Control animals were injected with the aluminum hydroxide suspension only. On days 55-57 of pregnancy, longitudinal uterine and cervical strips from guinea pigs were prepared for isometric tension recording. Nonpregnant guinea pigs were outfitted with telemetric transducers to record intrauterine pressure and uterine electromyography. Ovalbumin significantly increased contractility of uterine and cervical strips from sensitized versus nonsensitized animals. These effects were abolished by histamine H(1) receptor antagonist in uterine strips and by histamine H(1) receptor antagonist and a mast cell stabilizer in cervical strips from sensitized animals. Cyclooxygenase and 5-lipoxygenase inhibitors had no significant effect on the response to ovalbumin. Treatment with ovalbumin in vivo significantly increased intrauterine pressure and uterine electromyography activity in sensitized but not in nonsensitized, animals. Our findings indicate that type I hypersensitivity reactions may be important in mediating uterine contractility in pregnant and nonpregnant states.

Determination of Adsorbed Protein Concentration in Aluminum Hydroxide Suspensions by Near-Infrared Transmittance Spectroscopy

Analysis of aluminum hydroxide based vaccines is difficult after antigen adsorption. Adsorbed protein is often assessed by measuring residual unadsorbed protein for quality control. A new method for the direct determination of adsorbed protein concentration in suspension using near-infrared (NIR) transmittance spectroscopy is proposed here. A simple adsorption system using albumin from bovine serum (BSA) and aluminum hydroxide as a model system is employed. The results show that the NIR absorbance at 700-1300 nm is correlated to the adsorbed BSA concentration, measured by the ultraviolet (UV) method, using the partial least square regression (PLSR) method to construct a calibration model. The linear concentration range of adsorbed BSA is from 0 to 1.75 mg/mL by using 10 mm path length cuvettes. The influence of the sedimentation in suspension, different buffers, and different aluminum hydroxide batches was investigated in this study. It shows that the batch variation is the main influence factor of this method, while the buffer variation has no influence. However, the pretreatment of spectral data by subtracting spectra of BSA blank control (aluminum hydroxide without BSA) can significantly reduce the batch influence, and the NIR predicted results show good agreement with the reference values. The NIR method might be the only direct method for the determination of adsorbed protein concentration in suspension so far. It is a nondestructive method, and it has great advantage for use in vaccine production as a method for quality control and quality assurance.

Enhancing the Immune Response

Although aluminum-containing adjuvants are widely used in vaccines, the mechanisms whereby they potentiate the immune response have been unclear. Various agents with adjuvant activity stimulate maturation of dendritic cells (DCs), which are critical to activating adaptive immune responses; however, in vitro studies have not found any effect of aluminum-containing adjuvants on DC maturation. Kool et al . used mice that had received fluorescently labeled T cells that recognized ovalbumin (OVA) to establish that OVA emulsified with a suspension of aluminum hydroxide and magnesium hydroxide (OVA-alum) elicited a larger and more prolonged immune response than did OVA alone. Intraperitoneal (i.p.) injection of OVA-alum stimulated the rapid recruitment to the peritoneal cavity of inflammatory monocytes as well as a later increase in myeloid and plasmacytoid DCs, neutrophils, and eosinophils. OVA-alum stimulated more OVA uptake and processing by peritoneal CD11c + DCs than did OVA. Further, it stimulated DC maturation, ability to stimulate T cell proliferation, and migration to draining lymph nodes. Indeed, OVA-alum stimulated OVA uptake by inflammatory monocytes and their stimulation of T cell proliferation, as well as their migration to draining lymph nodes, expression of CD11c, and conversion to DCs. Depletion of DCs resident in specific lymph nodes abolished stimulation of T cell proliferation in those nodes by i.p. OVA, but not OVA-alum, whereas systemic depletion of CD11c + cells during immunization abolished OVA-alum’s adjuvant activity. Unlike saline or OVA, i.p. injection of OVA-alum increased peritoneal uric acid concentration. Uricase abolished OVA-alum–dependent recruitment of inflammatory monocytes to lymph nodes (also lost in mice lacking MyD88, which has been implicated in the inflammatory response to uric acid) and its adjuvant effect. The authors thus conclude that the immunostimulatory activity of aluminum-containing adjuvants depends on activation of DCs by uric acid. M. Kool, T. Soullié, M. van Nimwegen, M. A. M. Willart, F. Muskens, S. Jung, H. C. Hoogsteden, H. Hammad, B. N. Lambrecht, Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J. Exp. Med. 205 , 869-882 (2008). [Abstract] [Full Text]

Determination of aluminium content in aluminium hydroxide formulation by FT-NIR transmittance spectroscopy

A method for determining the aluminium content of an aluminium hydroxide suspension using near infrared (NIR) transmittance spectroscopy has been developed. Inductively coupled plasma-atomic emission spectroscopy (ICP-AES) was used as reference method. The factors influencing the NIR analysis, such as different sample containers (transmission cell and cuvette), sedimentation in the suspension, day-to-day variation and batch-to-batch variation have been studied before constructing a calibration model. Seven dilutions (0–4100 mg Al/L) of five batches of aluminium hydroxide suspension samples were measured by NIR transmission each on five different days, with total of 175 spectra used for the calibration set. The multivariate data analysis technique partial least square regression (PLSR) was applied to build the calibration model. Six batches of aluminium hydroxide samples were used for the test set. ICP-AES and NIR transmittance spectroscopy exhibit comparable precision and accuracy. The NIR method provides several advantages: no complicated sample preparation; easy to operate; fast and non-destructive. In conclusion, NIR transmittance spectroscopy can be an alternative analytical method for determining aluminium content in aluminium hydroxide suspension.

Particle Size Determination in Aluminum Hydroxide Suspensions Using Near-Infrared Transmittance Spectroscopy

A new method for particle size determination in polystyrene and aluminum hydroxide suspensions using near-infrared transmittance spectroscopy is described. Mono-dispersed polystyrene particle size standards were used to establish the calibration model. The particle sizes used in the study are similar to the wavelength range of 700-1300 nm, where light scattering is wavelength dependent. The wavelength dependency of near-infrared (NIR) absorbance is found to be linear with the particle size when the analysis is based on the same spectrum starting point (the same absorbance at 700 nm). Partial least squares regression (PLSR) is applied to model this linear relationship. Compared to laser diffraction (LD) the NIR method has similar accuracy and precision in the measurement of particles with a uniform size. For a sample containing multiple sizes of particles, the mean size measured by the NIR method is shown to be weighted by the particle mass. The application of the model to aluminum hydroxide suspension shows that the NIR method is suitable for the detection of particle size changes during the production process and storage. The advantages of the NIR method are that no knowledge of the refractive index and the concentration of a sample are necessary and that the method is fast and easy to operate.

Radiation-induced esophagitis: A double-blind randomized clinical trial of aluminum hydroxide plus magnesium hydroxide plus oxetacaine suspension versus aluminum hydroxide plus magnesium hydroxide suspension

9100 Background: To assess whether oral administered oxetacaine-containing suspension is effective in treating acute radiation- induced esophagitis in cancer patients. Methods: A double-blind, prospective-randomized clinical trial was conducted across 20 radiotherapy institutions in Germany. Patients [pts.] with head and neck or thoracic cancer without dysphagia/odynophagia received definitive or postoperative radiotherapy [RT] with or without chemotherapy including at least 5 cm of the esophagus in the high dose volume. Pts. were randomized to receive oral aluminum hydroxide plus magnesium hydroxide plus oxetacaine (Tepilta [T]) suspension or aluminum hydroxide plus magnesium hydroxide suspension without oxetacaine (Magaldrat [M]) as first-line treatment for acute radiation-induced esophagitis. Primary endpoint was the interval between begin of RT and failure of first-line treatment of esophagitis defined as need for additional systemic analgesics. Data on pts.’ symptoms were collected during and for at least 2 weeks after treatment. Results: A total of 158 pts. were randomized, of whom 103 had take at least one dose of the study medication for acute esophagitis = grade 2 (CTC). Of the 105 pts., 51 were randomized to receive T and 52 M. The cumulative incidence of acute esophagitis = grade 2 (CTC) was 25% for the T and 22% for the M arm. Kaplan-Meier analysis showed a statistically significant difference between the two groups regarding the need for systemic analgesics under consideration of the intake time in favor of T (p = 0.032). No statistically significant difference was found between the two groups regarding the secondary endpoints need respective delay of additional parenteral nutrition (p = 0.28 respective p = 0.12), and pts.`s and investigator`s estimation of global effectivity of the study medication (0.08 and 0.12). Conclusions: This trial demonstrated a statistically significant delay of the intake time for systemic analgesics in pts. randomized to receive oral aluminum hydroxide plus magnesium hydroxide plus oxetacaine suspension. No significant financial relationships to disclose.

Interactions of Bovine Serum Albumin with Aluminum Polyoxocations and Aluminum Hydroxide

Interactions of aqueous solutions of aluminum polyoxocations (Al13-mers and Al30-mers) and aluminum hydroxide suspensions of varying particle sizes (26, 55, and 82 nm) with a model protein, bovine serum albumin (BSA), have been investigated using potentiometry, conductometry, viscometry, 27Al solution NMR, UV-vis spectroscopy, dynamic light scattering, zeta-potential measurements, thermogravimetry, X-ray diffraction, and scanning electron microscopy. Increasing amounts of BSA partially convert Al13-mers and, to a larger extent, Al30-mers into amorphous Al hydroxide without gel formation. At the same time, BSA molecules can form unstable aggregates in the Al polyoxocation solutions which redisperse easily upon standing. In the case of Al hydroxide sols, BSA addition causes substantial gelation, the extent of which is proportional to the amount of BSA added and inversely related to the Al hydroxide particle size. Upon freeze-drying or centrifugation of Al species-BSA solutions, an interesting sheetlike morphology with 150-200 nm wide nanoribbons is observed for pure Al hydroxide nanoparticles and for solutions of Al polyoxocations with the highest amount of BSA studied. On the basis of the combined solution, colloidal and solid-state characterization of model Al species-BSA systems, a qualitative model of possible interactions in the Al polyoxocation-BSA and Al hydroxide-BSA systems is proposed wherein core-shell hybrid nanoparticles are formed from protein "core" and Al polyoxocation "shell" or Al hydroxide "core" and protein "shell".