Avoid missing pKas: High-throughput workflow using solution pH-metric in tandem with UV-metric measurements.

We describe a new high-throughput automated pKa workflow using potentiometry starting with 10 mM DMSO stock (solution pH-metric). Two approaches using either neat DMSO stock solution or removal of DMSO were evaluated with different sample amounts and cosolvent schemes. These were validated against traditional potentiometric measurements for optimal conditions. Further, we detail how high throughput solution pH-metric experiments are performed in tandem with established UV-metric measurements to capitalize on the advantages of both approaches. This new workflow maintains the sample and time savings required for measuring a large number of samples in a drug discovery setting, while avoiding "missing pKas" due to lack of sufficient UV chromophores. The combination of the two assays is key to tackle the challenges of low solubility, overlapping pKas, and preliminary assignment of pKas for Structure-Activity Relationship (SAR) understanding.

Efficacy and safety of ambroxol hydrochloride in the treatment of secretory otitis media: a systematic review and meta-analysis.

Background: Secretory otitis media is a very common nonsuppurative inflammatory disease in otorhinolaryngology. Ambroxol hydrochloride helps to improve ciliary movement in the ear canal and promote the dissolution and discharge of secretions. However, its effect still lacks systematic evaluation. We conducted a meta-analysis of clinical studies to systematically evaluate the application effect of ambroxol hydrochloride. Methods: A computer-based search of the Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), PubMed, and Web of Science databases was conducted using the keywords "Ambroxol hydrochloride" & "secretory otitis media". Randomized controlled trials published after 2015 were selected and then screened and analyzed using RevMan 5.4 software. Results: Ten studies involving a total of 998 patients were included. Meta-analysis showed that adding ambroxol hydrochloride to the original glucocorticoid treatment improved therapeutic efficacy [odds ratio (OR) =4.95, 95% confidence interval (CI): 3.27, 7.50, P<0.00001], reduced tympanic pressure after treatment [mean difference (MD) =-19.04, 95% CI: -22.72, -15.36, P<0.00001], and increased the pure tone threshold (MD =6.37, 95% CI: 5.36, 7.37, P<0.00001), without increasing adverse reactions (OR =0.51, 95% CI: 0.14, 1.85, P=0.30). Discussion: On the basis of the original treatment of secretory otitis media, adding ambroxol hydrochloride treatment improved the therapeutic effect, reduced tympanic pressure after treatment, and improved the pure tone threshold (hearing), without increasing adverse reactions.

Acupuncture for hearing loss after traumatic brain injury: A protocol for systematic review of randomized controlled trial.

BACKGROUND: This study aims to systematically assess the effectiveness and safety of acupuncture on hearing loss (HL) after traumatic brain injury (TBI). METHODS: In this study, the following databases will be retrieved from inception up to the May 1, 2019: PUBMED, EMBASE, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, and Chinese Biomedical Literature Database. All databases will be retrieved without any language restrictions. Two reviewers will independently carry out article selection, data collection, and risk of bias evaluation. Any disagreements will be solved by a third reviewer through discussion. RESULTS: This study will systematically investigate the effectiveness and safety of acupuncture for treating HL after TBI through evaluating HL assessment, hearing threshold, quality of life, and adverse events. CONCLUSION: The expected findings of this study will provide latest evidence for assessing the effectiveness and safety of acupuncture for HL after TBI. ETHICS AND DISSEMINATION: This study is supposed to be published in a peer-reviewed journal. No ethical approval is needed because this study will based on the literature analysis, but not the individual patient. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019133417.

Efficacy of mometasone furoate for nasal polyps: A protocol for systematic review of randomized controlled trial.

BACKGROUND: This study aims to systematically explore the efficacy and safety of mometasone furoate (MTF) for patients with nasal polyps (NP). METHODS: We will search MEDLINE, Cochrane Library, PubMed, Springer, Web of Science, Ovid, Wangfang and Chinese Biomedical Literature Database from their inception to April 30, 2019 without language restrictions. All randomized controlled trials (RCTs) of MTF for the treatment of NP will be considered for inclusion. RevMan 5.3 software will be used for data synthesis, subgroup analysis, sensitivity analysis, as well as the meta-analysis. RESULTS: Primary outcomes include change in symptom scores (as measured by any symptom scores), and polyp size (as assessed by any Polyp size scores or tools). Secondary outcomes consist of polyp recurrence, change in nasal air flow, quality of life outcomes (as measured by any quality of life scales, such as Short Form Health Survey is a 36-item), and adverse events. CONCLUSION: This study will provide evidence for judging whether MTF is an effective and safe treatment for NP or not. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019134037.

Neuromuscular electrical stimulation on hearing loss caused by skull base fracture: A protocol for systematic review of randomized controlled trial.

BACKGROUND: This systematic review aims to investigate the effectiveness and safety of neuromuscular electrical stimulation (NMES) on hearing loss (HL) caused by skull base fracture (SBF). METHODS: We will retrieve the following electronic databases of Cochrane Library, PUBMED, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, and Chinese Biomedical Literature Database from the inception to January 1, 2019 for relevant RCTs of NMES for HL caused by SBF. Two experienced authors will independently perform the study selection, data extraction, and methodology quality assessment. A 3rd author will solve any disagreements between 2 authors through discussion. RESULTS: This study will provide a high-quality synthesis of latest evidence of NMES for HL caused by SBF from comprehensive assessments, including hearing loss evaluation, hearing threshold, quality of life, and any relevant adverse events. CONCLUSION: The expected results of this systematic review will provide the up-to-date evidence to assess the effectiveness and safety of NEMS for patients with HL caused by SBF. ETHICS AND DISSEMINATION: The results of this study will be disseminated through publication in a peer-reviewed journal or will be presented at an associated conference meeting. This study will not use individual patient data, thus, the ethical approval is not needed. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019120195.

Efficacy of transsphenoidal surgery for pituitary tumor: A protocol for systematic review.

BACKGROUND: This systematic review aims to assess the efficacy and safety of transsphenoidal surgery (TPS) for patients with a pituitary tumor (PT). METHODS: We will retrieve the following electronic databases for randomized controlled trials or case-control studies to assess the effect and safety of TPS for PT: Cochrane Library, EMBASE, MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Allied and Complementary Medicine Database, and Chinese Biomedical Literature Database. Each database will be retrieved from the inception to December 20, 2018. The entire process consists of the study selection, data collection, methodology quality assessment, data pooled, and meta-analysis performance. The methodology quality will be assessed by using Cochrane risk of bias tool. The data pooled and meta-analysis will be conducted by using RevMan 5.3 software. RESULTS: This study will evaluate the efficacy and safety of TPS for PT. The primary outcome includes total tumor resection rate. The secondary outcomes consist of quality of life, total tumor resection rate, postoperative complication rate, and the rate of functional tumor hormone levels. CONCLUSION: The expected results may provide up-to-date evidence of TPS for the treatment of PT. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42018120194.

Acupuncture as an add-on therapy to sublingual allergen-specific immunotherapy for patients with allergic rhinitis.

This study retrospectively analyzed the effectiveness of acupuncture as add-on therapy (AAOT) to sublingual allergen-specific immunotherapy (SASIT) for patients with allergic rhinitis (AR). A total of 120 eligible cases of adult patients with AR were included in this retrospective study. Of these, 60 patients received AAOT plus SASIT and were assigned to a treatment group, while the other 60 subjects underwent SASIT only, and were assigned to a control group. Primary outcome was AR symptoms. The secondary outcome was quality of life, as evaluated by the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). In addition, adverse events were also recorded during the study period. All outcomes were assessed before and after 8 weeks treatment. After 8 weeks treatment, patients in the treatment group had much better effectiveness in symptoms relief (P <.05), and quality of life improvement (activity domain, P = .04; practical domain, P = .03), compared with patients in the control group. In addition, although patients in the treatment group reported more mild pain at local area after the treatment than that in the control group (P <.01), no patients stopped the treatment. The results of this study showed that AAOT plus SASIT achieved more benefits in patients with AR than SASIT alone.

Interactions between ß2-Adrenoceptor Ligands and Membrane: Atomic-Level Insights from Magic-Angle Spinning NMR.

To understand the relationship between structural properties of the ß2-adrenoceptor ligands and their interactions with membranes, we have investigated the location and distribution of five ß2 agonists with distinct clinical durations and onsets of action (indacaterol, two indacaterol analogues, salmeterol and formoterol) in monounsaturated model membranes using magic angle spinning NMR to measure these interactions through both 1H nuclear Overhauser enhancement (NOE) and paramagnetic relaxation enhancement (PRE) techniques. The hydrophilic aromatic groups of all five ß2 agonists show maximum distribution in the lipid/water interface, but distinct location and dynamic behavior were observed for the lipophilic aromatic rings. Our study elucidates at atomic level that the hydrophobicity and substitution geometry of lipophilic groups play important roles in compound-lipid interactions.

[Sedum sarmentosun bunge extraction ameliorated severe acute pancreatitis-induced lung injury: an experimental research]].

OBJECTIVE: To explore the effect of Sedum sarmentosum Bunge Extract (SSBE) on severe acute pancreatitis (SAP) induced acute lung injury (ALI) model rats and their excessive inflammatory reactions. METHODS: Forty-two healthy adult male Sprague-Dawley (SD) rats were randomly divided into 3 groups, the sham-operated control group (C), the SAP group (SAP), and the SSBE treated group (SSBE), 14 in each group. SAP induced ALl rat model was induced by retrograde injection of 5% sodium taurocholate (1 mL/kg) into the pancreatic duct. SSBE (100 m/kg) was administrated subcutaneously after the establishment of the SAP model. Equal dose of SSBE was injected again 12 h later. Equal volume of normal saline was administrated in the same way for rats in the C group and the SAP group. Rats were sacrificed after successful modeling and samples taken at 12 and 24 h. Pathological changes in the pancreas and the lung tissue were observed under light microscope. The ascites, serum amylase (AMS), wet/dry proportion (W/D) of the lung tissue, activities of myeloperoxidase (MPO), interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were also measured. RESULTS: Ascites and serum AMS activities significantly increased; MPO, IL-1, IL-6, TNF-alpha contents, and W/D ratio also significantly increased in the SAP group, when compared with the C group (P<0.05). Compared with the SAP group, those parameters were all attenuated in the SSBE group at 12 and 24 h (P<0.05, P<0.01). Pathological changes in the pancreas and the lung tissue were alleviated in the SSBE group under light microscope. The injury degree ranged between that of the C group and the SAP group. CONCLUSION: SSBE could relieve the ALl in SAP model rats, which could be achieved through alleviating inflammation responses of SAP rats.

Predicting phospholipidosis: a fluorescence noncell based in vitro assay for the determination of drug-phospholipid complex formation in early drug discovery.

This paper describes for the first time, a high-throughput fluorescence noncell based assay to screen for the drug-phospholipid interaction, which correlates to phospholipidosis. Anionic amphiphilic phospholipids can form complexes in aqueous solution, and its critical micelle concentration (CMC) can be determined using the fluorescence probe N,N-dimethyl-6-propionyl-2-naphthylamine (Prodan). Upon interaction with drug candidates, this CMC may shift to a lower value due to the association between lipids and drug candidates, the stronger the interaction, the greater the shift. Metabolism of a drug can change the degree of phospholipidosis depending on the rate of metabolism and the nature of the metabolite(s). Our data from 45 drugs and metabolites of 10 drugs using this fluorescence approach demonstrate a good correlation with phospholipidosis as reported with human studies, in vivo testing, and cellular assays. This assay therefore offers a fast, reliable, and cost-effective screening tool for early prediction of the phospholipidosis-inducing potential of drug candidates.

[Expression and the role of HIF-1alpha and VEGF in human nasal epithelial cells].

OBJECTIVE: To observe the expression and the role of hypoxic inducible factor-1alpha and VEGF induced by infection factor, inflammatory factor and hypoxia in primary human nasal epithelial cell (HNEC). METHOD: Epithelial cells of nasal polyps (NP) and inferior turbinate (IT) were cultured without serum under stimulus of LPS10, 100, 1000 microg/L, IL-1beta 20 microg/L and hypoxia for 3 h, 6 h, 9 h, respectively. The expression of HIF-1alpha and VEGF protein and mRNA derived from epithelial cells was detected by immunocytochemistry and in situ hybridization. RESULT: 1) Under hypoxia, EPO mRNA was expressed intensely in epithelial cells from NP and IT, and there was no significant difference between both of them. This result suggested that EPO might be regarded as a hypoxic mark; 2) The expression of HIF-1alpha and VEGF increased under the stimulus of infection factor, inflammatory factor and hypoxia with the increasing of time and concentration, especially in hypoxia (P<0.05); 3) The expression of HIF-1alpha and VEGF expressed more intensively in epithelial cells from NP than IT under all conditions (P<0. 05); 4) There was positive correlation between the expression of HIF-1alpha and VEGF (r=0.870, P<0.05). CONCLUSION: Epithelial cells actively produce vast HIF-1alpha and VEGF under infection factor, inflammatory factor and hypoxia. HIF-1alpha and VEGF are involved in the formation of nasal polyps.

Development of a high throughput equilibrium solubility assay using miniaturized shake-flask method in early drug discovery.

Increasingly, pharmaceutical and biotech companies have begun to realize the importance of obtaining solubility information in early drug discovery as it is one of the critical parameters for lead selection and optimization. This report introduces a high-throughput equilibrium solubility (HT-Eq sol) assay using a novel miniaturized shake-flask approach and streamlined HPLC analysis. The new HT-Eq sol assay, validated and optimized via a test set of 85 marketed drugs and Novartis internal compounds, shows an excellent correlation to the conventional shake-flask thermodynamic solubility data generated in-house and the equilibrium solubility results reported in literature. It therefore offers a fast, reliable and cost-effective screening tool for solubility assessment in early drug discovery, allowing for prioritization of drug candidates using aqueous solubility in conjunction with other profiling information and efficacy data. Our work demonstrates that presence of a small amount of DMSO (0.5-5%) will result in significant overstimation of equilibrium solubility (up to 6 folds). In addition, monitoring of drug dissolution process using the current approach as well as the interplay between equilibrium solubility data and those from kinetic solubility are discussed.

[Methacillin resistant Staphylococcus aureus pneumonia complicated with septicemia, multiple aneurysms and arterial thrombosis: a case report and review of the literature].

OBJECTIVE: To improve the understanding of the clinical manifestations of complications caused by methacillin resistant Staphylococcus aureus (MRSA) pneumonia. METHODS: A case of MRSA pneumonia complicated by septicemia, multiple aneurysms and arterial thrombosis was reported, and the literature was reviewed. The pathogenesis of MRSA septicemia, aneurysm and arterial thrombosis was discussed. RESULTS: A 66 year old male was admitted to this hospital because of fever, cough and sputum production for 1 month. The temperature on admission was 40 degrees C. Blood cultures for 2 times and sputum cultures all grew MRSA. The diagnosis of community acquired MRSA pneumonia and septicemia was made. The temperature returned normal after intravenous vancomycin therapy. But localized fever, pain and pulsating masses were noted, and ultrasonography and CT scanning revealed aneurysm formation in the external iliac arteries and the bilateral superior gluteal arteries, and arterial thrombi in the bilateral femoral arteries and deep femoral arteries. CONCLUSIONS: MRSA pneumonia complicated with multiple aneurysm and arterial thrombosis is uncommon. Endothelial injury caused by arteritis may lead to blood coagulation, and vascular muscle injury can cause or aggravate arterial dilatation and aneurysm.